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Biomedical subjects

M Moore

Publications and source records attributed to M Moore.

At least 19 recordsLinked to original sources
PubMed1998

Mobilization and harvesting of peripheral blood stem cells: randomized evaluations of different doses of filgrastim.

The effects of different doses of filgrastim on yields of CD34+ peripheral blood stem cells were evaluated in patients with breast cancer. 55 were randomized to receive filgrastim 10, 20, 30 or 40 microg/kg/d with more CD34+ cells/kg/apheresis harvested after the three highest dose levels. 35 additional patients were randomized to receive 10 or 30 microg/ kg. The median number of CD34+ cells collected after 10 microg/ kg (n = 31) was 0.7 x 10(6)/kg/apheresis (range 0.1-4.4) as compared to 1.2 (range 0.1-6.8) after 30 microg/kg (n = 32) (P = 0.04). Among patients randomized to 10 v 30 microg/kg, more (50%) achieved > or = 5.0 x 10(6) CD34+ cells/kg and less aphereses were required to achieve > or = 2.5 x 10(6) CD34+ cells/kg after the higher dose (P = 0.04). In multivariate analyses, patients receiving 10 microg/kg (n = 31) had lower yields of CD34+ cells (P = 0.026) and had a 3.3-fold increase in the probability of not achieving > or = 5.0 x 10(6) CD34+ cells/kg as compared to patients receiving 20-40 microg/kg (n = 59). Patients who had received radiation had a 2.9-fold probability of not achieving > or = 2.5 x 10(6) CD34+ cells/kg. These data suggest that, in patients with good marrow reserves, doses of filgrastim > 10 microg/kg/d mobilized more CD34+ cells and may be useful when high numbers of CD34+ cells are desired.

Antigens, CD34↗
PubMed1998

Management of stage II seminoma.

PURPOSE: To assess the results of treatment, patterns of failure, and prognostic factors for relapse in a contemporary cohort of patients with stage II seminoma. MATERIALS AND METHODS: From January 1981 and December 1993, 99 patients (median age, 35 years) with stage II seminoma (IIA, 41; IIB, 28; IIC, 24; IID, six) were managed at our institution. Eighty were treated with radiation therapy (RT) and 19 with chemotherapy (ChT). RESULTS: With a median follow-up of 6.7 years, the five-year overall actuarial survival was 94%, the 5-year cause-specific survival was 94%, and the 5-year relapse-free rate was 83%. Sixteen (20%) of the 80 patients treated with RT relapsed (median time to relapse, 9 months). Relapse occurred outside the irradiated area in all but two patients. Distant relapse sites included the supraclavicular fossa, bone (four patients, three with spinal cord compression), and lung/mediastinum. All 19 patients treated primarily with ChT achieved disease control and none has relapsed. The relapse rate at 5 years for patients with stage IIA to IIB was 11% (seven of 64), and 56% (nine of 16) for those with stage IIC to IID disease (P < .0001). No patient with IIC or IID disease treated with ChT relapsed as compared with 56% of patients treated with RT (0 of 14 v nine of 16, P = .002). CONCLUSION: Radiation therapy is highly effective in patients with stage IIA or IIB seminoma (89% were relapse free). In stage IIC or IID disease, although local control with RT is excellent, a 50% risk of distant relapse is unacceptable, and not all patients who relapse can be salvaged. Chemotherapy should clearly be the primary treatment in patients with stage IIC or IID seminoma.

Adult↗
PubMed1997

Trends in drug-resistant tuberculosis in the United States, 1993-1996.

CONTEXT: With the resurgence of tuberculosis (TB) disease in the late 1980s and early 1990s in the United States, multidrug-resistant (MDR) TB emerged as a serious challenge to TB control. In response, the Centers for Disease Control and Prevention in 1993 added drug susceptibility test results to the information collected for the national surveillance system to monitor trends in drug resistance. OBJECTIVE: To determine the extent of drug-resistant tuberculosis (TB) in the United States. DESIGN: Descriptive analysis of TB surveillance data. STUDY POPULATION: Patients reported to the national TB surveillance system as confirmed TB cases with culture-positive disease from 1993 through 1996 by the 50 states, New York City, and the District of Columbia (DC). MAIN OUTCOME MEASURE: Percentage of case patients with culture-positive disease whose isolates are resistant to specific anti-TB drugs. RESULTS: Overall resistance to at least isoniazid was 8.4%; rifampin, 3.0%; both isoniazid and rifampin (ie, MDR TB), 2.2%; pyrazinamide, 3.0%; streptomycin, 6.2%; and ethambutol hydrochloride, 2.2%. Rates of resistance were significantly higher for case patients with a prior TB episode. Among those without prior TB, isoniazid resistance of 4% or more was found in 41 states, New York City, and DC. A total of 1457 MDR TB cases were reported from 42 states, New York City, and DC; however, 38% were reported from New York City. Rates of isoniazid and streptomycin resistance were higher for cases among foreign-born compared with US-born patients [corrected] but rates of rifampin resistance and MDR TB were similar. Among US-born patients, resistance to first-line drugs, particularly rifampin monoresistance, was significantly higher among those with human immunodeficiency virus (HIV) infection. CONCLUSIONS: Compared with recent US surveys in 1991 and 1992, isoniazid resistance has remained relatively stable. In addition, the percentage of MDR TB has decreased, although the national trend was significantly influenced by the marked decrease in New York City. Foreign-born and HIV-positive patients and those with prior TB have higher rates of resistance. The widespread extent of isoniazid resistance confirms the need for drug susceptibility testing to guide optimal treatment of patients with culture-positive disease.

Antitubercular Agents↗
PubMed1997

Characterization of tumor necrosis factor-deficient mice.

Although tumor necrosis factor (TNF) initially came to prominence because of its anti-tumor activity, most attention is now focused on its proinflammatory actions. TNF appears to play a critical role in both early and late events involved in inflammation, from localizing the noxious agent and amplifying the cellular and mediator responses at the local site and systemically, to editing (e.g., apoptosis) injured cells or effete immune cells and repairing inflammatory damage. We have generated mice deficient in TNF (TNF-/- mice) and have begun to examine the multiple functions attributed to TNF. TNF-/- mice develop normally and have no gross structural or morphological abnormalities. As predicted, they are highly susceptible to challenge with an infectious agent (Candida albicans), are resistant to the lethality of minute doses of lipopolysaccharide (LPS) following D-galactosamine treatment, have a deficiency in granuloma development, and do not form germinal centers after immunization. Phagocytic activity of macrophages appears relatively normal, as do T cell functions, as measured by proliferation, cytokine release, and cytotoxicity. B cell response to thymus-independent antigens is normal, but the Ig response to thymus-dependent antigen is reduced. Surprisingly, cytokine production induced by LPS appears essentially intact, with the exception of reduced colony-stimulating factor activity. Other unexpected findings coming from our initial analysis are as follows. (i) TNF has low toxicity in TNF-/- mice. (ii) TNF-/- mice show an anomalous late response to heat-killed Corynebacterium parvum. In contrast to the prompt response (granuloma formation, hepatosplenomegaly) and subsequent resolution phase in C. parvum-injected TNF+/+ mice, similarly treated TNF-/- mice show little or no initial response, but then develop a vigorous, disorganized inflammatory response leading to death. These results suggest that TNF has an essential homeostatic role in limiting the extent and duration of an inflammatory process-i.e., an anti-inflammatory function. (iii) In contrast to the expectation that TNF+/+ mice and TNF+/- mice would have identical phenotypes, TNF+/- mice showed increased susceptibility to high-dose LPS lethality, increased susceptibility to Candida challenge, and delayed resolution of the C. parvum-induced inflammatory process, indicating a strong gene dose requirement for different actions of TNF.

Animals↗
PubMed1997

Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus.

A serum glycoprotein, Gc protein (vitamin D3-binding protein), can be converted by beta-galactosidase of B cells and sialidase of T cells to a potent macrophage-activating factor (MAF), a protein with N-acetylgalactosamine as the remaining sugar moiety. Thus, Gc protein is the precursor for MAF. Treatment of Gc protein with immobilized beta-galactosidase and sialidase generates a remarkably high titered macrophage-activating factor (GcMAF). When peripheral blood monocytes/ macrophages (designated macrophages) of 33 systemic lupus erythematosus patients were incubated with GcMAF (100 pg/ml), the macrophages of all patients were activated as determined by superoxide generation. However, the precursor activity of patient plasma Gc protein was lost or reduced in these patients. Loss of the precursor activity was the result of deglycosylation of plasma Gc protein by alpha-N-acetylgalactosaminidase activity found in the patient plasma. Levels of plasma alpha-N-acetylgalactosaminidase activity in individual patients had an inverse correlation with the MAF precursor activity of their plasma Gc protein. Deglycosylated Gc protein cannot be converted to macro-phage-activating factor. The resulting defect in macro-phage activation may lead to an inability to clear pathogenic immune complexes. Thus, elevated plasma alpha-N-acetylgalactosaminidase activity resulting in the loss of MAF precursor activity and reduced macro-phage activity may play a role in the pathogenesis of systemic lupus erythematosus.

Adolescent↗
PubMed1997

Antiestrogenic activity of hydroxylated polychlorinated biphenyl congeners identified in human serum.

Several hydroxylated polychlorinated biphenyls (PCBs) identified in human serum have been synthesized and these include 2,2',3,4',5,5'-hexachloro-4-biphenylol; 2,3,3',4',5-pentachloro-4-biphenylol; 2',3,3',4',5-pentachloro-4-biphenylol; 2,2',3,3',4',5-hexachloro-4-biphenylol; 2,2',3,3',4',5,5'-heptachloro-4-biphenylol; 2,2',3,4',5,5',6-heptachloro-4-biphenylol; and 2,2',3',4,4',5,5'-heptachloro-3-biphenylol. The hydroxy-PCBs exhibited minimal binding to the rat uterine cytosolic estrogen receptor (ER) and did not induce proliferation of estrogen-responsive MCF-7 human breast cancer cells at concentrations ranging from 10(-5) to 10(-8) M. The estrogenic activity of these compounds was further investigated utilizing two estrogen-responsive in vitro bioassays, namely, (i) HeLa cells stably transfected with a Gal4:human ER chimera and a 17-mer-regulated luciferase reporter gene, and (ii) MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a chloramphenicol acetyl transferase (CAT) reporter gene. None of the hydroxy-PCBs significantly induced luciferase activity in the stably transfected HeLa cells or CAT activity in MCF-7 cells at concentrations as high as 10(-5) M. The antiestrogenic effects of the hydroxy-PCBs were also investigated using the same bioassays in which the cells were cotreated with 17beta-estradiol plus the hydroxy-PCBs. All of the hydroxy-PCB congeners inhibited one or more estrogenic response, and one congener, 2,2',3,4',5,5',6-heptachloro-4-biphenylol, inhibited 17beta-estradiol-induced cell proliferation and CAT activity in MCF-7 cells and luciferase activity in HeLa cells.

Adenocarcinoma↗
PubMed1997

Hydroxylated polychlorinated biphenyls (PCBs) as estrogens and antiestrogens: structure-activity relationships.

The effects of structure on the estrogenicity and antiestrogenicity of hydroxylated polychlorinated biphenyls were investigated using the following estrogen-sensitive assays: competitive binding to the rat and mouse cytosolic estrogen receptor (ER); immature rat and mouse uterine wet weight, peroxidase and progesterone receptor (PR) levels; induction of luciferase activity in HeLa cells stably transfected with a Gal4:human ER chimera and a 17mer-regulated luciferase reporter gene; proliferation of MCF-7 human breast cancer cells; induction of chloramphenicol acetyl transferase (CAT) activity in MCF-7 cells transiently transfected with a full-length human ER expression plasmid and a plasmid containing an estrogen-responsive vitellogenin A2 promoter linked to a CAT reporter gene. The chemicals synthesized for this study contained a 4-hydroxy group in one ring, a 2- or 3-chloro substituent meta or ortho to the hydroxyl group, and variable substitution (2',3',4',5'-, 2',3',4',6'-, 2',3',5',6'-tetrachloro and 2',4',6'-trichloro) in the chlorophenyl ring. The compounds included: 2,2',3',4',5'- (A), 2,2',3',4',6'- (B), and 2,2',3',5',6'-pentachloro- (C); 2,2',4',6'-tetrachloro-4-biphenylol (D); 2',3,3',4',5'- (E), 2',3,3',4',6'- (F), and 2',3,3',5',6'-pentachloro (G); and 2',3,4',6'-tetrachloro-4-biphenylol (H). With the exception of 2',3,4',6'-tetrachloro-4-biphenylol (H), all of the compounds competitively bound to the mouse and rat ER with relative binding affinities [compared to 17beta-estradiol (E2)] varying from 1.4 x 10(-3) to 5.3 x 10(-5). The structure-ER binding relationships for the hydroxy-PCB congeners were different in the rat and mouse, and no dose-dependent estrogenic activities were observed in the mouse or rat uterus. Several hydroxy-PCB congeners exhibited antiestrogenic activity (primarily in the mouse uterus) and two compounds, 2,2',3',5',6- and 2,2',3',4',6'-pentachloro-4-biphenylol, inhibited E2-induced uterine wet weight, PR binding, and peroxidase activity in the mouse uterus. 2,2',3',4',5'- and 2,2',3',4',6'-Pentachloro-4-biphenylol induced CAT activity in MCF-7 cells transiently transfected with the Vit-CAT plasmid; the remaining congeners did not induce CAT activity but exhibited antiestrogenic activity in MCF-7 cells cotreated with 10(-9) E2 plus 10(-5) M hydroxy-PCBs. Complementary structure-estrogenicity relationships were observed utilizing the HeLa cell luciferase induction and MCF-7 cell proliferation assays. The placement of the 2- or 3-chloro groups in the phenolic ring had minimal effects on estrogenic activity, whereas 2,4,6-trichloro- and 2,3,4,6-tetrachloro substitution in the chlorophenyl ring (B, D, F, and H) were required for this response. Substitution in the phenolic ring was also not important for structure-antiestrogenicity relationships, and the most active compounds (A, C, E, and G) contained 2',3',4',5'- and 2',3',5',6'-tetrachlorophenyl groups. Thus, structure-estrogenicity/antiestrogenicity relationships for this series of hydroxy-PCBs were complex and response-specific.

Animals↗
PubMed1997

Respective role of TNF receptors in the development of experimental cerebral malaria.

The respective role of the two receptors of TNF in experimental cerebral malaria (CM) was investigated. During CM, a significant upregulation of TNF-receptor 2 (TNFR2), but not of TNFR1, was found in brain microvessels of susceptible, but not resistant mice. Mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from CM, while TNFR1-deficient (Tfnr1null) mice were as susceptible as wild-type mice. The protection of Tnfr2null mice could be explained by their absence of ICAM-1 upregulation and leukocyte sequestration, known to occur in brain microvessels of CM-susceptible animals.

Animals↗
PubMed1997

Will natural products remain an important source of drug research for the future?

In the highly competitive environment of contemporary pharmaceutical research, natural products provide a unique element of molecular diversity and biological functionality which is indispensable for drug discovery. The emergence of strategies to deliver drug leads from natural products within the same time frame as synthetic chemical screening has eliminated a major limitation of the past. At a more functional level, the application of molecular genetics techniques has permitted the manipulation of biosynthetic pathways for the generation of novel chemical species as well as rendering hitherto uncultivatable microorganisms accessible for secondary metabolite generation. These developments augur well for an industry confronted with the challenge of finding lead compounds directed at the plethora of new targets arising from genomics projects. The exploitation of structural chemical databases comprising a wide variety of chemotypes, in conjunction with databases on target genes and proteins, will facilitate the creation of new chemical entities through computational molecular modelling for pharmacological evaluation.

Biotechnology↗
PubMed1997

Plasma membrane water permeability of cultured cells and epithelia measured by light microscopy with spatial filtering.

A method was developed to measure the osmotic water permeability (Pf) of plasma membranes in cell layers and applied to cells and epithelia expressing molecular water channels. It was found that the integrated intensity of monochromatic light in a phase contrast or dark field microscope was dependent on relative cell volume. For cells of different size and shape (Sf9, MDCK, CHO, A549, tracheal epithelia, BHK), increased cell volume was associated with decreased signal intensity; generally the signal decreased 10-20% for a twofold increase in cell volume. A theory relating signal intensity to relative cell volume was developed based on spatial filtering and changes in optical path length associated with cell volume changes. Theory predictions were confirmed by signal measurements of cell layers bathed in solutions of various osmolarities and refractive indices. The excellent signal-to-noise ratio of the transmitted light detection permitted measurement of cell volume changes of <1%. The method was applied to characterize transfected cells and tissues that natively express water channels. Pf in control Chinese hamster ovary cells was low (0.0012 cm/s at 23 degrees C) and increased more than fourfold upon stable transfection with aquaporins 1, 2, 4, or 5. Pf in apical and basolateral membranes in polarized epithelial cells grown on porous supports was measured. Pfbl and Pfap were 0.0011 and 0.0024 cm/s (MDCK cells), and 0.0039 and 0.0052 cm/s (human tracheal cells) at 23 degrees C. In intact toad urinary bladder, basolateral Pf was 0.036 cm/s and apical membrane Pf after vasopressin stimulation was 0.025 cm/s at 23 degrees C. The results establish light microscopy with spatial filtering as a technically simple and quantitative method to measure water permeability in cell layers and provide the first measurement of the apical and basolateral membrane permeabilities of several important epithelial cell types.

Animals↗
PubMed1997

Pharmacokinetics and metabolism of the novel anticonvulsant agent N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in rats and humans.

N-(2,6-dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) belongs to a new series of experimental anticonvulsants related to lidocaine. This study was undertaken to understand the pharmacokinetics and metabolism of D2624 in rats and humans, with emphasis on the possible formation of 2,6-dimethylaniline (2,6-DMA). After oral administration of stable isotope-labeled parent drug to rats and GC/MS analysis of plasma samples, two metabolites were identified: D3017, which is the primary alcohol, and 2,6-DMA, formed by amide bond hydrolysis of either D2624 or D3017. In urine, three metabolites of D2624 were identified: namely D3017,2,6-DMA, and D3270 (which is the carboxylic acid derivative of D3017). Based on plasma AUC analysis, D3017 and 2,6-DMA accounted for > 90% of the dose of D2624. After oral administration, D2624 was found to be well absorbed (93%), but underwent extensive first-pass metabolism in the rat, thus resulting in 5.3% bioavailability. Rat and human liver microsomal preparations were capable of metabolizing D2624 to D3017 and 2,6-DMA. The formation of D3017 was NADPH-dependent, whereas 2,6-DMA formation was NADPH-independent and probably was catalyzed by amidase(s) enzymes. In a single-dose (25-225 mg) human volunteer study, the parent drug (D2624) was not detected in plasma at any dose, whereas 2,6-DMA was detected only at the two highest doses (150 and 225 mg). D3017 was detected after all doses of parent drug, with approximate dose proportionality in AUC and a half-life of 1.3-2.2 hr. The metabolic behavior observed in humans suggests there is a marked species difference in the oxidative and hydrolytic pathways of D2624.

Aniline Compounds↗
PubMed1997

Prognostic factors for relapse in stage I testicular seminoma treated with surveillance.

PURPOSE: We sought to identify prognostic factors predictive of disease progression in patients with clinical stage I seminoma on surveillance following orchiectomy. MATERIALS AND METHODS: Between January 1981 and December 1993, 201 patients 20 to 86 years old (median age 34) with clinical stage I seminoma were placed on surveillance following orchiectomy. The potential prognostic factors studied included age, tumor size, mitotic count, S phase fraction, ploidy, presence of small vessel invasion, syncytiotrophoblasts and tumor infiltrating lymphocytes, expression of beta-human chorionic gonadotropin and low molecular weight keratin on immunohistochemistry. RESULTS: With a median followup of 6.1 years (range 1.3 to 12.3) 31 patients had relapse for an actuarial 5-year relapse-free rate of 84.9%. The 5-year actuarial survival rate was 97.1% and the cause specific survival rate was 99.5%. On univariate analysis factors predictive of relapse were tumor size (5-year relapse-free rate 88 and 67% for tumors 6 cm. or less and greater than 6 cm., respectively, p = 0.004), age (5-year relapse-free rate 79 and 91% for age 34 years or younger versus older than 34 years, respectively, p = 0.009) and presence of small vessel invasion (5-year relapse-free rate 86 versus 69%, p = 0.01). On multivariate analysis age and tumor size were predictive of relapse, while small vessel invasion approached statistical significance. The risk of relapse in 57 patients with none of the 3 adverse prognostic factors (age greater than 34 years, tumor 6 cm. or smaller and no small vessel invasion) was 6%. CONCLUSIONS: We identified age, size of the primary tumor and small vessel invasion as important prognostic factors for relapse in patients with stage I seminoma treated with surveillance. Further followup and assessment of biological factors are needed to optimize selection of patients at a high risk for relapse who should receive immediate postoperative therapy.

Actuarial Analysis↗
PubMed1997

Management of hepatic artery injury: case report.

The trauma surgeon encounters hepatic arterial injury only rarely. The majority of these injuries appear to be due to penetrating trauma, with few cases of hepatic artery injury secondary to blunt trauma reported in the literature. In the setting of blunt trauma, hepatic artery injury is generally accompanied by other severe injuries, and mortality remains high. We present two patients who sustained an avulsion of the left hepatic artery complicating severe blunt trauma to the abdomen and pelvis. Surgical management included ligation of the involved vessel. Both patients required management in the intensive care unit, one eventually succumbing to multisystem organ failure. The cases highlight management principles in these injuries, and treatment options are discussed.

Abdominal Injuries↗
PubMed1997

Contact lens use after corneal trauma.

BACKGROUND: This study was performed to explore the epidemiology and visual outcomes of major anterior segment trauma cases referred to the Contact Lens Service (CLS) in a large, urban, eye trauma center at a university hospital. METHODS: All eye trauma patients seen on the CLS at The University of Illinois in Chicago for a 2-year period were identified (n = 122). A search of all eye trauma cases seen at UIC (n = 2279) during the same period yielded 757 cases with the same diagnostic codes. RESULTS: CLS cases represent 16.1% of cases with similar diagnoses and 5.35% of all cases seen during the period of study. Cases were predominantly young men (mean age, 28 years). The mean age for CLS cases (mean age, 17 years) was significantly younger. Best-corrected visual acuity was 20/100 or better in 75% of cases with a contact lens and in 68% of cases with a spectacle lens; 82% of CLS cases had iris damage versus 14.5% of non-CLS cases; 73% of CLS cases were aphakic; 105 CLS cases were given contact lenses. Mean follow-up time was 24 months. Mean wearing time was 11 hours/day. On interview, 35 of 79 cases (44%) continued to wear lenses. CONCLUSIONS: Cases referred to the CLS tended to be young men with unilateral injuries-predominantly open globes-with resultant aphakia and iris damage. Good visual acuity was achieved in most cases. Long-term success wearing contact lenses for this population was poor, suggesting that alternatives to contact lens wear should be more actively considered.

Adolescent↗
PubMed1997

The role of HIV counseling and testing in the developing world.

The role of voluntary HIV counseling and testing is still under debate, especially in the developing world. HIV counseling-and-testing (HIV CT) services are a major component of HIV and AIDS control programs in the industrialized world and are increasingly being advocated in the developing world. In the United States, voluntary HIV CT has been a major component of HIV prevention efforts since the HIV antibody test became available in 1985. Yet even in the United States, questions about the management, cost, and effectiveness of voluntary HIV CT services continue to be raised. Because HIV CT has multiple goals, the evaluation of its effectiveness is a complicated task. Worldwide, a broad range of ethical, social, policy, technical, and economic issues encompass this HIV prevention activity. This article identifies the substantial barriers and serious concerns that are raised about HIV CT services and attempts to highlight the potential advantages of providing HIV CT as part of a developing country's comprehensive HIV prevention strategy.

AIDS Serodiagnosis↗