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W Alexander

Publications and source records attributed to W Alexander.

At least 19 recordsLinked to original sources
PubMed2001

Application of statistical models for secondary data usage of the US Navy's Occupational Exposure Database (NOED).

Many organizations around the world have collected data related to individual worker exposures that are used to determine compliance with workplace standards. These data are often warehoused and thereafter rarely used as an information resource. Using appropriate groupings and analysis of OSHA data, Gómez showed that such stored data can provide additional insight on factors affecting occupational exposures. Using data from the Occupational Exposure Database of the United States Navy, the usefulness of statistical models for defining probabilities of exposure above permissible limits for observed work conditions is examined. Analyses have highlighted worker Similar Exposure Groups (SEGs) with potential for overexposure to asbestos and lead. In terms of grouping data, Rappaport et al. defined the Within-Between Lognormal Model, a scale-independent measure for quantifying between-worker variability within a selected worker group: (B)R.95 = exp[3.92s(sB)], representing the ratio of arithmetic mean exposures received by workers in the 97.5th and 2.5th percentiles. To help search for groups, the Proportional Odds Model, a generalization of the logistic model to ordinal data, can predict probabilities for group exposure above the Occupational Exposure Limit (OEL), or the Action Level (AL), which is one-half of the OEL. Worker SEGs have been identified for asbestos workers removing friable asbestos ((B)R.95 = 11.0) and nonfriable asbestos ((B)R.95 = 6.5); metal cleaning workers sandingspecialized equipment ((B)R.95 = 11.3), and workers at target shooting ranges cleaning up lead debris ((B)R.95 = 10). Estimated probabilities for the categories OEL support current understanding of work processes examined. Differences in probability noted between tasks and levels of ventilation validate this method for evaluating other available workplace exposure determinants, and for predicting probability of membership in categories that may help further define worker exposure groups, and determinants of excessive exposures. Thus, analyses of retrospective exposure data can help identify work site and work practice factors for efficient targeting of remediation resources.

Databases, Factual↗
PubMed2001

Systemic p53 gene therapy of cancer with immunolipoplexes targeted by anti-transferrin receptor scFv.

BACKGROUND: A long-standing goal in genetic therapy for cancer is a systemic gene delivery system that selectively targets tumor cells, including metastases. Here we describe a novel cationic immunolipoplex system that shows high in vivo gene transfer efficiency and anti- tumor efficacy when used for systemic p53 gene therapy of cancer. MATERIALS AND METHODS: A cationic immunolipoplex incorporating a biosynthetically lipid-tagged, anti-transferrin receptor single-chain antibody (TfRscFv), was designed to target tumor cells both in vitro and in vivo. A human breast cancer metastasis model was employed to evaluate the in vivo efficacy of systemically administered, TfRscFv-immunolipoplex-mediated, p53 gene therapy in combination with docetaxel. RESULTS: The TfRscFv-targeting cationic immunolipoplex had a size of 60-100 nm, showed enhanced tumor cell binding, and improved targeted gene delivery and transfection efficiencies, both in vitro and in vivo. The p53 tumor suppressor gene was not only systemically delivered by the immunolipoplex to human tumor xenografts in nude mice but also functionally expressed. In the nude mouse breast cancer metastasis model, the combination of the p53 gene delivered by the systemic administration of the TfRscFv-immunolipoplex and docetaxel resulted in significantly improved efficacy with prolonged survival. CONCLUSIONS: This is the first report using scFv-targeting immunolipoplexes for systemic gene therapy. The TfRscFv has a number of advantages over the transferrin (Tf) molecule itself: (1) scFv has a much smaller size than Tf producing a smaller immunolipoplex giving better penetration into solid tumors; (2) unlike Tf, the scFv is a recombinant protein, not a blood product; (3) large scale production and strict quality control of the recombinant scFv, as well as scFv-immunolipoplex, are feasible. The sensitization of tumors to chemotherapy by this tumor-targeted and efficient p53 gene delivery method could lower the effective dose of the drug, correspondingly lessening the severe side effects, while decreasing the possibility of recurrence. Moreover, this approach is applicable to both primary and recurrent tumors, and more significantly, metastatic disease. The TfRscFv-targeting of cationic immunolipoplexes is a promising method of tumor targeted gene delivery that can be used for systemic gene therapy of cancer with the potential to critically impact the clinical management of cancer.

Animals↗
PubMed2000

Rapid separation of nitroaromatic compounds by solvating gas chromatography.

Nitroaromatic compounds such as 2,4,6-trinitrotoluene are used in the production of explosive and munitions, and are environmental contaminants as a result of such use. Conventional methods to detect these compounds have relied on liquid and gas chromatography to isolate the individual compounds which may be present at low levels in complex environmental matrices before final detection and identification. A new method, solvating gas chromatography, was used to rapidly separate 8 nitroaromatic compounds, showing improved speed relative to conventional liquid and gas chromatography methods. Solvating gas chromatography allows near real-time detection for these energetic compounds, providing improvements in their detection as environmental contaminants, and as compounds of interest to law enforcement and military organizations.

Chromatography, Gas↗
PubMed2000

The quality of care for Medicare patients with peptic ulcer disease.

OBJECTIVE: The aim of this study was to examine quality of care for hospitalized Medicare beneficiaries with peptic ulcer disease. METHODS: Collaborating with five Peer Review Organizations, we used 1995 Medicare claim files to select samples of inpatients with a principal diagnosis of peptic ulcer disease. Quality of care indicators developed by content experts included percentages for ulcer patients tested for Helicobacter pylori (H. pylori); biopsied patients who received tissue tests; H. pylori-positive patients who received appropriate therapy; and ulcer patients screened for preadmission nonsteroidal anti-inflammatory drug (NSAID) use and counseled about risks. RESULTS: Of 2,644 patients eligible for medical record review, 56% were tested for H. pylori, and 73% of those testing positive were treated appropriately; 84% of patients with endoscopic biopsies received a tissue test for H. pylori; 74% of patients were screened for preadmission NSAID use, 24% had documented counseling of NSAID use, and only 2% had documented counseling on the ulcer risk of NSAID use. Statistically significant regional variation occurred in four of six quality indicators. Outpatient records were reviewed for 529 patients to document prior outpatient H. pylori in this population; only 2% (n = 12) were tested for H. pylori in the year before admission. CONCLUSIONS: Opportunities exist to improve quality of care by testing for and treating H. pylori in hospitalized Medicare beneficiaries with peptic ulcer disease and to improve screening for NSAIDs and counseling on ulcer risks.

Aged↗
PubMed1999

Autologous blood transfusion does not reduce postoperative infection rates in elective surgery.

BACKGROUND: The influence of blood transfusions in the risk of postoperative infection remains controversial. We examined the association between autologous (AB) and homologous (HB) blood transfusions with postoperative infection in elective surgery. METHODS: The medical records of 991 Medicare patients aged > or =65 years submitted to hysterectomy and hip and knee replacement were reviewed. Logistic regression analysis was used to control for age, comorbidity, year, and type of procedure. RESULTS: Overall, 451 (46%) patients required transfusions. AB was given to 324 (72%), HB to 94 (21%); 33 (7%) patients received both. Forty-two patients (4%) developed postoperative infections. The infection rate was not different among patients receiving HB (7%), AB (5%), AB+HB (0), and nontransfused patients (4%); P = 0.18). After adjustment for confounders, HB and AB remained not associated with infections. CONCLUSION: In elective surgery with small volume transfusion, neither AB nor HB transfusions were associated with an increased risk of postoperative infections.

Aged↗
PubMed1999

Conjugation of 7-oxodehydroabietic acid to lysine, a haptenation mechanism for an oxidized resin acid with dermal sensitizing properties.

This article explores protein conjugation of 7-oxodehydroabietic acid, a resin acid found in both aerosol from soldering with rosin flux and in rosin solids. In a murine model, conjugation (haptenation) of resin acids to proteins is required to generate antibodies against rosin. Hydroperoxy resin acids are dermal sensitizers, with haptenation thought to occur via radical mechanisms. Dermal sensitization to 7-oxodehydroabietic acid has been observed, although no radical haptenation mechanism has been proposed to explain the sensitizing properties of this compound. Conjugation of L-lysine to 7-oxodehydroabietic acid was predicted, with a Schiff base (or imine) linkage formed between C-7 of the resin acid and a free amino group of lysine. Fast atom bombardment mass spectrometry provided evidence of the conjugate; a small peak was seen for the conjugate (M+H)+ ion in aqueous ethanol with 20 mM concentrations of the free resin and amino acids. A larger conjugate peak was observed with addition of tertiary amine as a mild basic catalyst, and the intensity of the conjugate peak exceeded that of the precursors upon replacement of the ethanol with benzene. Resin acids accumulate in the plasma membrane, a non-aqueous environment apparently conducive to conjugation of 7-oxodehydroabietic acid with lysine side chains of membrane proteins. The result would be dehydroabietic acid covalently bound to protein, which could lead to interaction with immune cells having resin acid specificity. The haptenation mechanism presented may be involved in allergic contact dermatitis and occupational asthma observed from exposure to resin acid solids and aerosols. As sampling and analytical methods have been previously demonstrated for 7-oxodehydroabietic acid, this compound may be a useful exposure marker with relevance to negative health effects such as occupational asthma.

Abietanes↗
PubMed1999

Chemical detection in deployment toxicology using high speed gas chromatography with a solvating mobile phase and time-of-flight mass spectrometry.

Solvating gas chromatography (SGC) involves a mobile phase that is a supercritical fluid at the column inlet (typically 100-350 atm) and a gas upon exiting the column at ambient pressure. SGC has characteristics of both supercritical fluid chromatography and gas chromatography, and may be adaptable to a system with characteristics approaching a "universal chromatograph" capable of analyzing many classes of compounds on one instrument. We have recently found that using a solvating mobile phase such as CO2, together with small, spherical particle-packed capillary columns can offer significant advantages for rapid chemical analysis. A need exists in operational military settings to rapidly detect a wide range of chemicals with potential adverse health effects for exposed personnel. A separation step improves analytical capability by reducing or eliminating chemical background for better detection limits, and purifies or isolates target analytes and unknowns for improved identification. SGC, coupled to a high volume vapor/aerosol sampler and a rapid mass spectrometric detector such as a time-of-flight mass spectrometer could provide rapid, positive identification of separated compounds, with the resulting chromatographic and mass spectral data stored in digital format for future retrieval. Such a system will significantly advance the ability of military commanders to detect airborne chemical agents rapidly and accurately, protecting the health of military personnel.

Chemical Warfare Agents↗
PubMed1998

Genetic stability of Sabin 1 strain of poliovirus: implications for quality control of oral poliovirus vaccine.

The Sabin vaccine strains of poliovirus, like all RNA viruses, exist as a quasispecies of genomic sequences whose composition can be altered during virus propagation. Since changes in vaccine virus during manufacture can enhance the neurovirulent potential of the vaccine, each monovalent lot of oral poliovirus vaccine (OPV) undergoes several tests to ensure consistency of manufacture, including the monkey neurovirulence test (MNVT). Recently, we proposed a new molecular approach for direct quantification of vaccine variants with neurovirulent potential as an alternative way to monitor consistency of OPV production. Analysis of the Sabin 1 genome allowed us to identify a limited number of specific loci that exhibit significant change during viral propagation in vitro and in vivo. Here we explore the possible roles of these changes and show that 7427-U-->C and 7441-G-->A alterations in the 3'-UTR of the Sabin 1 virus do not increase monkey neurovirulence. These, as well as our previous results, suggest that only mutations in the 5'-UTR play a significant role in the limited increase in Sabin 1 monkey neurovirulence observed after extended propagation of the virus beyond the passage level used in vaccine production. Our studies with high-passage batches of the Sabin 1 strain confirmed the stability of this strain, which retains acceptable levels of monkey neurovirulence even after serial passages at elevated temperature. Compared to the MNVT, molecular analysis of the genetic composition of Sabin 1 poliovirus provides a more sensitive analytical approach to monitor consistency of vaccine production.

Animals↗
PubMed1998

The biological consequences of excess GM-CSF levels in transgenic mice also lacking high-affinity receptors for GM-CSF.

GM-CSF transgenic mice were crossed with mice with homozygous inactivation of the gene encoding the common beta chain (beta c) of the GM-CSF receptor to produce mice with constitutively elevated GM-CSF levels but no high-affinity GM-CSF receptors. GM-CSF transgenic beta c -/- mice had exceptionally elevated serum GM-CSF levels but failed to develop the abnormal peritoneal cell population, eye destruction or tissue lesions characteristic of GM-CSF transgenic beta c +/+ mice. The alveolar proteinosis of beta c -/- mice was not altered in GM-CSF transgenic beta c -/- mice. Levels of GM-CSF mRNA in transgenic GM-CSF beta c -/- were elevated but lower than in transgenic beta +/+ mice and the higher serum GM-CSF levels were traced in part to the longer serum half-life of GM-CSF in beta c -/- than in beta c +/+ mice although urinary loss of GM-CSF was higher in beta c -/- than in +/+ mice. The data indicate that the transgenic phenotype was due to stimulation by GM-CSF and not an insertional effect, that low-affinity receptors are not capable of initiating tissue pathology even in the presence of excess GM-CSF levels and that autocrine production of GM-CSF by GM-CSF-responsive cells also fails to induce changes in these cells. The results support current dogma that the action of polypeptide regulators is mediated exclusively by activation of high-affinity membrane receptors.

Animals↗
PubMed1998

CSF-1 and interferon-gamma act synergistically to promote differentiation of FDC-P1 cells into macrophages.

FDC-P1 cells expressing the wildtype CSF-1 receptor, FDwtfms, differentiate into macrophages during incubation with CSF-1. This response is amplified in the presence of interferon-gamma. Cells expressing the 807F mutant receptor, 807F cells, proliferate in response to CSF-1 and do not differentiate. However, in response to CSF-1 and interferon-gamma they differentiate as well. CSF-1 causes the activation of STAT proteins in FDwtfms cells, but not in 807F cells. Cellular differentiation correlates with a sustained activation of STAT1 and STAT3 in response to interferon-gamma over at least 40 hours. However, interferon-gamma alone did not cause differentiation of cells expressing either receptor. Other defects in response to CSF-1 of the 807F cells, such as lack of PLC gamma 2 activation, were not complemented by co-incubation of the cells with CSF-1 and interferon-gamma. It appears that a combination of signaling pathways are activated by CSF-1 and interferon-gamma which caused the shift of response from proliferation to differentiation in the 807F cells and an enhanced differentiation in the FDwtfms cells.

Animals↗
PubMed1995

A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation.

The mutant mouse waved-2 (wa-2) is strikingly similar to transforming growth factor alpha-deficient mice generated by gene targeting in embryonic stem cells. We confirm that wa-2 is a point mutation (T-->G resulting in a valine-->glycine substitution at residue 743) in the gene encoding the epidermal growth factor (EGF) receptor. wa-2 fibroblastic cells lack high-affinity binding sites for EGF, and the rate of internalization of EGF is retarded. Although the tyrosine kinase activity of wa-2 EGF receptors is significantly impaired, NIH 3T3 cells lacking endogenous EGF receptors but overexpressing recombinant wa-2 EGF receptor cDNA are mitogenically responsive to EGF. While young and adult wa-2 mice are healthy and fertile, 35% of wa-2 mice born of homozygous wa-2 mothers die of malnutrition because of impaired maternal lactation.

3T3 Cells↗
PubMed1995

Endemic work-related febrile respiratory illness among construction workers.

Construction workers building Denver International Airport (DIA) reported work-related respiratory and flulike symptoms of several months duration. We performed a cross-sectional interview study of 495 randomly selected DIA workers from six contractors in comparison with preplacement workers. We defined cases as workers with two work-attributed lower respiratory symptoms and one work-attributed systemic symptom. Case rates were significantly higher among DIA workers (34%) compared with those who had never worked at DIA (2%). Risk factors for illness included exposure to fireproofing (OR, 4.21; 95% CI, 1.95-9.08), work in tunnels and adjoining areas (OR, 3.07; 95% CI, 1.84-5.12), length of DIA employment (OR, 0.65; 95% CI, 0.46-0.92), and preexisting bronchitis (OR, 2.43; 95% CI, 1.17-5.05). Our industrial hygiene investigation revealed alkaline dust (pH 11) present at a worksite associated with elevated risk of illness, and we identified airborne Penicillium mold widely distributed indoors at DIA. Clinical evaluation of 26 self-identified symptomatic DIA employees, including bronchoalveolar lavage and biopsy in 10, revealed work-related asthma in three workers and histologic evidence of chronic bronchitis in four who had never smoked. We concluded that future investigations of endemic work-related febrile respiratory illness among construction workers should evaluate its association with indoor exposure to dusts from alkaline fireproofing, Penicillium mold, mycotoxins, and bacterial bioaerosols.

Adult↗