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Biomedical subjects

L A Miller

Publications and source records attributed to L A Miller.

At least 55 records · Page 3Linked to original sources
PubMed2000

A comparative In vitro surveillance study of gemifloxacin activities against 2,632 recent Streptococcus pneumoniae isolates from across Europe, North America, and South America. The Gemifloxacin Surveillance Study Research Group.

From 1997 to 1999, 94 study centers in 15 European, 3 North American, and 2 South American countries contributed 2,632 isolates of Streptococcus pneumoniae to an international antimicrobial susceptibility testing study. Only 62.0% of isolates were susceptible to penicillin, while 22.3% were penicillin intermediate and 15.6% were penicillin resistant. Resistance to trimethoprim-sulfamethoxazole (24.4%), azithromycin (26.0%), and clarithromycin (27.1%) was also highly prevalent. For the penicillin-resistant isolates (n = 411), the MICs at which 90% of isolates are inhibited (MIC(90)s) for gemifloxacin, levofloxacin, ofloxacin, clarithromycin, and azithromycin were 0.03, 1, 2, >16, and >64 microgram/ml, respectively. Similarly, for isolates resistant to both azithromycin and clarithromycin (n = 649), gemifloxacin, levofloxacin, ofloxacin, and penicillin MIC(90)s were 0.03, 1, 2, and 4 microgram/ml, respectively. Overall rates of resistance to trovafloxacin (0.3%), levofloxacin (0.3%), grepafloxacin (0.6%), and ofloxacin (0.7%) were low. For ofloxacin-intermediate and -resistant isolates (n = 142), gemifloxacin had the lowest MIC(90) (0.12 microgram/ml) compared to the MIC(90)s of trovafloxacin (0.5 microgram/ml), grepafloxacin (1 microgram/ml), and levofloxacin (2 microgram/ml). For all S. pneumoniae isolates tested, gemifloxacin MICs were </=0.5 microgram/ml, suggesting that gemifloxacin has the potential to be used as a treatment for pneumococcal infections, including those arising from isolates resistant to beta-lactams and macrolides.

Adolescent↗
PubMed2000

Trafficking of neutrophils across airway epithelium is dependent upon both thioredoxin- and pertussis toxin-sensitive signaling mechanisms.

Leukocyte recruitment from the circulation into the airways is a multi-step process, involving both chemotactic and adhesive mechanisms. Using an in vitro model of leukocyte transepithelial trafficking, we show that movement of human peripheral blood neutrophils (PMN) across airway epithelium in the optimal basolateral-to-apical surface direction is partially blocked by pertussis toxin, an inhibitor of G(alphai)-protein-linked receptors. A neutralizing monoclonal antibody against interleukin-8 (IL-8; constitutively expressed by airway epithelium) did not inhibit PMN transepithelial migration, suggesting that alternative pertussis toxin-sensitive signaling mechanisms are involved in this process. However, a neutralizing antibody against thioredoxin, a redox enzyme with pertussis toxin-insensitive chemoattractant activity, did reduce PMN migration across airway epithelium. We conclude that trafficking of PMN across airway epithelium is mediated by both thioredoxin- and pertussis toxin-sensitive signaling mechanisms that are independent of IL-8.

Cell Movement↗
PubMed1999

Long-term effects of PZP immunization on reproduction in white-tailed deer.

A 6-year study was conducted to determine the long-term effects of porcine zona pellucida (PZP) vaccine on the immune and hormonal responses, and reproduction of the white-tailed deer. The first 2 years of active immunization resulted in an 89% reduction in fawning. Vaccination with PZP produced reversible infertility lasting 1-4 years. Infertility was directly related to immune titers to PZP. Doe fertility was restored when the antibody titer dropped to minimal levels, but following re-immunization, infertility was reestablished. Reduction in fawning throughout the 6-year study was 76%. It was also observed that immune responses among deer were variable, especially in the first year of treatment. Variability was also observed among deer for the duration of infertility following the initial vaccination.

Animals↗
PubMed1999

The engagement of beta1 integrins on promonocytic cells promotes phosphorylation of Syk and formation of a protein complex containing Lyn and beta1 integrin.

The protein-tyrosine kinase Syk participates in signal transduction pathways downstream from multiple immune recognition receptors. Recent evidence indicates that Syk is also functionally coupled to cell surface integrins, which mediate interactions between the actin cytoskeleton and extracellular matrix proteins. The interactions of undifferentiated, promonocytic HL60 or U937 cells with fibronectin or anti-beta1 integrin antibodies leads to an apparent activation and tyrosine phosphorylation of Syk that is independent of tight cellular adhesion and spreading. In response to fibronectin or anti-beta1 integrin antibodies, beta1 integrins become associated with a complex of proteins that include the Lyn protein tyrosine kinase and endogenous kinase substrates of 29 and 75-80 kDa. Lyn becomes transiently activated following integrin engagement and co-localizes with the actin cytoskeleton. These studies suggest a major role for Lyn in coupling beta1 integrins to the activation of Syk.

Actins↗
PubMed1999

Inhibition of transforming growth factor beta production by nitric oxide-treated chondrocytes: implications for matrix synthesis.

OBJECTIVE: Nitric oxide (NO) is generated copiously by articular chondrocytes activated by interleukin-1beta (IL-1beta). If NO production is blocked, much of the IL-1beta inhibition of proteoglycan synthesis is prevented. We tested the hypothesis that this inhibitory effect of NO on proteoglycan synthesis is secondary to changes in chondrocyte transforming growth factor beta (TGFbeta). METHODS: Monolayer, primary cultures of lapine articular chondrocytes and cartilage slices were studied. NO production was determined as nitrite accumulation in the medium. TGFbeta bioactivity in chondrocyte- and cartilage-conditioned medium (CM) was measured with the mink lung epithelial cell bioassay. Proteoglycan synthesis was measured as the incorporation of 35S-sodium sulfate into macromolecules separated from unincorporated label by gel filtration on PD-10 columns. RESULTS: IL-1beta increased active TGFbeta in chondrocyte CM by 12 hours; by 24 hours, significant increases in both active and latent TGFbeta were detectable. NG-monomethyl-L-arginine (L-NMA) potentiated the increase in total TGFbeta without affecting the early TGFbeta activation. IL-1beta stimulated a NO-independent, transient increase in TGFbeta3 at 24 hours; however, TGFbeta1 was not changed. When NO synthesis was inhibited with L-NMA, IL-1beta increased CM concentrations of TGFbeta1 from 24-72 hours of culture. L-arginine (10 mM) reversed the inhibitory effect of L-NMA on NO production and blocked the increases in TGFbeta1. Anti-TGFbeta1 antibody prevented the restoration of proteoglycan synthesis by chondrocytes exposed to IL-1beta + L-NMA, confirming that NO inhibition of TGFbeta1 in IL-1beta-treated chondrocytes effected, in part, the decreased proteoglycan synthesis. Furthermore, the increase in TGFbeta and proteoglycan synthesis seen with L-NMA was reversed by the NO donor S-nitroso-N-acetylpenicillamide. Similar results were seen with cartilage slices in organ culture. The autocrine increase in CM TGFbeta1 levels following prior exposure to TGFbeta1 was also blocked by NO. CONCLUSION: NO can modulate proteoglycan synthesis indirectly by decreasing the production of TGFbeta1 by chondrocytes exposed to IL-1beta. It prevents autocrine-stimulated increases in TGFbeta1, thus potentially diminishing the anabolic effects of this cytokine in chondrocytes.

Animals↗
PubMed1999

A comparison of 18-MV and 6-MV treatment plans using 3D dose calculation with and without heterogeneity correction.

Homogeneity of the dose distribution in irradiation of the intact breast for stage I and II cancers is an important factor, particularly for larger breasts. In the present work, we have studied dose homogeneity for 6- and 18-MV treatment plans in 10 patients, typically with larger breasts. For each patient, 6 3-dimensional (3D) dose distributions were calculated using patient computed tomography data and the ADAC Pinnacle3 treatment planning system. First, a dose distribution was calculated, assuming the patient was water, with the 6-MV beam parameters used to treat the patient. Second, the calculation was repeated using the actual patient anatomy. Comparison of these 2 distributions showed how patient heterogeneity affected dose. Third, individual beam weights were optimized, and the dose calculation was repeated. Each of these 3 dose calculations was repeated at 18 MV. Results showed that: (1) at 6 MV, the ratio of mean dose in the target volume calculated with heterogeneity considerations to that without was 1.014 +/- 0.006, and the ratio of the standard deviation of dose in the target volume was 0.919 +/- 0.042; (2) at 18 MV, the ratio of mean dose to the target volume calculated with heterogeneity considerations to that without was 1.001 +/- 0.005, and the ratio of the standard deviation of dose in the target volume was 1.15 +/- 0.09; and (3) the dose homogeneity, measured by the standard deviation of the dose distribution in the target volume, was 25% less for the 18-MV treatment plan for patients with breast volumes greater than 1600 cm3. We conclude that: (1) 3D, heterogeneity-corrected dose calculation is necessary to fairly evaluate any advantage of 18 MV over 6 MV; (2) excluding the dose buildup region, 18 MV produces a significantly more homogeneous dose distribution for breast volumes greater than 1600 cm3; and (3) when prescribing dose using heterogeneity-corrected dose distributions, dose prescriptions should be increased by 1.5% at 6 MV, but no increase is needed for 18 MV.

Breast↗
PubMed1999

Differences between the activity of penicillin, amoxycillin, and co-amoxyclav against 5,252 Streptococcus pneumoniae isolates tested in the Alexander Project 1992-1996.

A number of published studies have shown that the MICs of amoxycillin and/or co-amoxyclav are lower than those of ampicillin and/or penicillin for Streptococcus pneumoniae. Other published studies have concluded that the activities of amoxycillin and co-amoxyclav are comparable with that of penicillin for S. pneumoniae. A collection of 5252 S. pneumoniae isolates obtained during a 5 year period (1992-1996) was analysed to determine differences between the MICs of penicillin, amoxycillin and co-amoxyclav. Among the isolates analysed, 3788 (72%) were penicillin-susceptible, 615 (12%) were penicillin-intermediate and 849 (16%) were penicillin-resistant. Differences between the agents were assessed by examination of MIC distribution functions and simultaneous 95% CIs. In addition, penicillin-intermediate and -resistant isolates were analysed to determine the number and percentage of isolates which had an amoxycillin and co-amoxyclav MIC less than, equal to, or greater than the penicillin MIC. Results showed that the amoxycillin and co-amoxyclav MIC90s were one two-fold dilution lower than those of penicillin for all isolates collected between 1992-1993 and 1994-1996. Simultaneous 95% CIs showed that the mean differences between MICs of amoxycillin and penicillin, and between MICs of co-amoxyclav and penicillin, were less than zero. The majority of the penicillin-intermediate and penicillin-resistant isolates had an amoxycillin and co-amoxyclav MIC less than the penicillin MIC. In conclusion, amoxycillin and co-amoxyclav MICs were shown to be lower than the penicillin MICs for the S. pneumoniae isolates analysed in this study.

Amoxicillin↗
PubMed1999

Oral vaccination of white-tailed deer using a recombinant Bacillus Calmette-Guérin vaccine expressing the Borrelia burgdorferi outer surface protein A: prospects for immunocontraception.

PROBLEM: Reduction of excess numbers of white-tailed deer (Odocoileus virginianus) is a prime example of a potential use for immunocontraception as a means of wildlife population management. Oral vaccination appears to be the most pragmatic way to deliver immunocontraceptive vaccines to free-roaming populations of deer, but there was little, if any, prior evidence that oral vaccination is a viable concept in deer. METHOD OF STUDY: We used live Bacillus Calmette-Guérin (BCG) in a recombinant form (rBCG), which expressed Borrelia burgdorferi outer surface protein A, to test whether deer vaccinated orally with a specific antigen expressed in a live vector produce detectable antibody titers. RESULTS: The data indicate that oral vaccination of deer with an expressed antigen is feasible, as demonstrated by peak antibody titers to the expressed antigen. Also, peak titers measured by enzyme-linked immunosorbent assay were highest in orally vaccinated deer: 1600 in deer vaccinated by injection and 6400 in those vaccinated orally. CONCLUSIONS: The results of this study demonstrate that it is feasible to vaccinate deer orally with a live vector.

Administration, Oral↗
PubMed1999

Escherichia coli ATCC 35218 as a quality control isolate for susceptibility testing of Haemophilus influenzae with haemophilus test medium.

Current National Committee for Clinical Laboratory Standards (NCCLS) susceptibility guidelines for quality control testing with Haemophilus influenzae do not include a beta-lactamase-producing strain that could detect the deterioration of the beta-lactamase inhibitor components of amoxicillin-clavulanic acid, ampicillin-sulbactam, and piperacillin-tazobactam. The objective of the study was to determine if comparable quality control results for Escherichia coli ATCC 35218, a beta-lactamase-producing strain, would be produced for the three beta-lactam-beta-lactamase inhibitor agents with Haemophilus test medium and Mueller-Hinton medium. The criteria used in this study to determine if Haemophilus test medium was acceptable for quality control testing of E. coli ATCC 35218 was that 100% of the results obtained with an antimicrobial agent-methodology combination needed to be within the acceptable NCCLS ranges established with Mueller-Hinton medium. The MIC testing results obtained by the broth microdilution and E-test methods with amoxicillin-clavulanic acid and piperacillin-tazobactam were all within the NCCLS ranges; however, the results obtained with ampicillin-sulbactam by both methods were not within the NCCLS ranges. Acceptable results were obtained by the disk diffusion methodology with ampicillin-sulbactam and piperacillin-tazobactam but not with amoxicillin-clavulanic acid. When performing susceptibility testing with H. influenzae with the beta-lactam-beta-lactamase inhibitors, in addition to quality control testing with H. influenzae ATCC 49247, testing of E. coli ATCC 35218 on Haemophilus test medium is an effective way to monitor the beta-lactamase inhibitors in some antimicrobial agent-methodology combinations.

Culture Media↗
PubMed1999

Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung injury in rhesus monkeys.

To test the hypothesis that neutrophil influx is important for the removal of necrotic airway epithelial cells, rhesus monkeys were treated with a function-blocking monoclonal antibody (MAb) against CD18 followed by exposure to ozone or filtered air. CD18 MAb-treated, ozone-exposed monkeys showed a significant inhibition of neutrophil emigration and an accumulation of necrotic airway epithelial cells. In a subsequent experiment, monkeys were given CD18 MAb or an isotype control immunoglobulin before ozone or filtered-air exposure. Complement 5a was instilled into lobes of the right lung at the end of the exposure. Lavage neutrophils were significantly elevated in the right lobes compared with those in the contralateral left lobes; consequently, there were significantly fewer necrotic cells in the airways of the right lung, whereas large aggregations of necrotic cells were observed in the contralateral airways of the left lung. These data indicate that neutrophil influx in ozone-induced injury in primates is CD18 dependent and that neutrophils contribute to the repair of airway epithelium by removal of injured epithelial cells.

Animals↗
PubMed1998

Generation of nitric oxide by lapine meniscal cells and its effect on matrix metabolism: stimulation of collagen production by arginine.

Slices of lapine meniscus produced large amounts of nitric oxide after stimulation with interleukin-1, tumor necrosis factor alpha, or a mixture of lapine synovial cytokines known as chondrocyte-activating factors. Monolayer cultures of meniscal cells produced from the proteolysis of meniscal tissue contained a mixed population of chondrocytic and fibroblastic cells. These cultures also produced large amounts of nitric oxide in response to cytokines. Monolayer cultures of meniscal cells produced by the explant method, in contrast, were uniformly fibroblastic and did not produce nitric oxide in response to cytokines. We conclude that menisci contain two populations of cells, one fibroblastic and the other chondrocytic. The chondrocytic cells are responsible for generating most of the nitric oxide in response to cytokines. Endogenously generated nitric oxide suppressed the synthesis of collagen and proteoglycan by menisci but protected proteoglycan from the catabolic effects of interleukin-1. The inhibitory effect of nitric oxide on collagen synthesis occurred without greatly altering the abundance of mRNAs encoding the various collagen alpha chains. During further investigation, arginine was unexpectedly found to stimulate the synthesis of collagen and, to a lesser degree, of noncollagenous proteins but not of proteoglycans. Fragments of meniscus, but not meniscal cells in monolayer culture, increased their production of matrix metalloproteinases, lactate, and, especially, prostaglandin E2 in response to interleukin-1. Inhibition of nitric oxide production with NG-monomethyl-L-arginine enhanced production of matrix metalloproteinases but had little effect on the synthesis of lactate or prostaglandin E2.

Animals↗
PubMed1998

Contributions of the entorhinal cortex, amygdala and hippocampus to human memory.

Recent studies have indicated that, in the monkey, the rhinal cortex (consisting of the entorhinal and perirhinal cortices) is more important to visual recognition memory than the hippocampus or amygdala. The present study investigated the role of the entorhinal cortex in humans using memory scores from surgical epilepsy patients classified according to their mesial temporal lobe pathology. The temporal lobe removals included 4-5 cm of neocortex, amygdala, rhinal cortex and 2-3 cm of the hippocampus and parahippocampal gyrus. Compared to autopsied control subjects, all of the patients showed significant gliosis in the amygdala, but they differed as to whether or not there were entorhinal and/or hippocampal abnormalities. Both preoperatively and one or more years postoperatively, the patients performed tests of verbal recall (Wechsler Memory Scale Logical Memory), visual recall (Rey Figure), verbal recognition and visual recognition (Warrington Recognition Memory Test: Words and Faces, respectively). Preoperatively, patients with hippocampal pathology showed deficits in visual recall. Postoperatively, a significant drop in verbal and visual recall was seen only for patients who lost intact hippocampal tissue, irrespective of the condition of the excised entorhinal cortex. Together, the results argue that the hippocampus is more important than the entorhinal cortex for the recall of newly learned information.

Adolescent↗
PubMed1998

Alternative splicing in wild-type AF10 and CALM cDNAs and in AF10-CALM and CALM-AF10 fusion cDNAs produced by the t(10;11)(p13-14;q14-q21) suggests a potential role for truncated AF10 polypeptides.

The t(10;11)(p13;q14-21) is a non-random translocation that occurs primarily in T cell acute lymphoblastic leukemias (T-ALL), but has also been observed in leukemias and lymphomas of diverse lineages. In U937, a cell line established from a diffuse histiocytic lymphoma, a t(10;11)(p13;q14-21) fuses AF10 to CALM. AF10 is also fused to MLL by a translocation that appears quite similar at the cytogenetic level, the t(10;11)(p12;q23). Fluorescence in situ hybridization studies have demonstrated that AF10 and CALM are also involved in other hematological malignancies containing t(10;11)(p13;q21), but no data are available concerning the molecular details of AF10-CALM fusion in primary leukemias. Using RT-PCR, we amplified multiple different isoforms of AF10-CALM and CALM-AF10 fusion cDNAs from a primary T cell ALL containing a t(10;11)(p13-14;q14-21). These cDNAs arose via alternative splicing of exons from both AF10 and CALM, which we demonstrated can also occur in the native genes. We identified at least two novel AF10 exons that can be included in wild-type and fusion cDNAs. The majority of the AF10 and AF10-CALM cDNA isoforms that we identified are predicted to encode for truncated AF10 polypeptides, raising the possibility that these might have important cellular functions in normal and malignant cells, perhaps by acting as dominant negative inhibitors of full-length AF10 or related proteins.

Adaptor Proteins, Vesicular Transport↗
PubMed1998

Inhibition of neurotensin-stimulated mast cell secretion and carboxypeptidase A activity by the peptide inhibitor of carboxypeptidase A and neurotensin-receptor antagonist SR 48692.

BACKGROUND: Neurotensin (NT), a peptide found in brain and several peripheral tissues, is a potent stimulus for mast cell secretion and its actions are blocked by the specific NT receptor antagonist, SR 48692. Subsequent to stimulation, NT is rapidly degraded by mast cell carboxypeptidase A (CPA). In the experiments described here, we tested for the involvement of CPA activity in the activation of mast cell secretion by the peptide, NT. METHODS: Mast cells were isolated from the peritoneal and pleural cavities of rats, purified over metrizamide gradients and incubated at 37 degrees C in Locke solution or Locke containing the appropriate inhibitors. For some experiments, media derived from mast cells stimulated by compound 48/80 were used as a source of mast cell CPA activity. RESULTS: Treatment of mast cells with the highly specific peptide inhibitor of CPA derived from potato (PCI) inhibited histamine release in response to NT and NT8-13 (the biologically active region of NT). This inhibition required some 20 min to develop and was only partially reversed by a 20-min wash period. PCI (10 microM) did not inhibit histamine release in response to NT1-12, bradykinin, compound 48/80, the calcium ionophore, A23187, or anti-IgE serum. PCI also inhibited mast cell CPA activity. SR 48692, a highly selective antagonist of the brain NT receptor and of NT-stimulated mast cell secretion, also inhibited mast cell CPA activity as well as bovine pancreatic CPA activity in a concentration-dependent manner. DISCUSSION: It is suggested that the mast cell binding site for NT and the active site for CPA may share similar characteristics. The results are discussed in terms of NT mechanism of action on the mast cell.

Animals↗
PubMed1998

Human airway epithelial monolayers promote selective transmigration of memory T cells: a transepithelial model of lymphocyte migration into the airways.

It has previously been demonstrated that T lymphocytes in the conducting airways express a pattern of adhesion molecules that are uniquely different from T lymphocytes found circulating in peripheral blood. To examine the role of airway epithelia in the determination of migratory capacity for human monocyte and lymphocyte populations in vivo, we have developed an in vitro transepithelial migration model using the human transformed bronchial epithelial cell line BEAS-2B S.6. In this study, we have demonstrated the preferential migration of human peripheral blood mononuclear cells (PBMC) across BEAS-2B S.6 cell monolayers in a physiologically appropriate direction (basal to apical epithelial cell surface). Stimulation of BEAS-2B S.6 cells with a combination of interferon-gamma and tumor necrosis factor-alpha upregulated basal-to-apical transepithelial migration by at least twofold. Monocytes migrated most efficiently, but subpopulations of CD19(+) B cells and CD2(+) cells were also recruited across epithelial cell monolayers. In the T lymphocyte subset of PBMC, CD45RO+ "memory" cells migrated preferentially. In addition, CD4(+) cells exhibited a significantly greater capacity to migrate across airway epithelium compared with CD8(+) cells. Migrated CD4(+) cells were predominantly CD29(high)/CD26(high), and within this subset uniformly expressed CD62L (L-selectin) at an intermediate level. PBMC migration across BEAS-2B S.6 cells was significantly inhibited by pertussis toxin; this result implicates a G protein signaling event as an important mediator of lymphocyte/monocyte transepithelial migration. On the basis of these data, we conclude that bronchial epithelium provides a unique microenvironment that supports the selective, G protein-dependent migration of memory T cells.

Bronchi↗
PubMed1998

Evaluation. Closing the loop.

After implementing a new nursing care delivery system, evaluating its outcomes is essential. An evaluation process answers key questions: (1) Were planned outcomes achieved? (2) Were the users satisfied? (3) Does the delivery system need to be modified?

Acute Disease↗