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Biomedical subjects

R Larson

Publications and source records attributed to R Larson.

At least 19 recordsLinked to original sources
PubMed1999

Quality beyond compliance.

The service sector within the biopharmaceutical industry has experienced phenomenal growth over the past decade. In the highly regulated Good Laboratory Practices environment, the need for timely, high-quality service, accurate results, and on-time deliverables becomes paramount for the success and profitability of biopharmaceutical companies. The quality assurance process is a vital component of this drug product-development cycle and ensures compliance to the highest domestic and international regulatory standards. Quality-assurance professionals historically have held the role of independent auditors of the processes, who certify that results meet current standards of practice. Covance, a contract research organization that includes Good Laboratory Practices laboratories, reorganized and expanded the functional responsibilities of its quality assurance team in 1997. Auditors and quality assurance professionals have assumed roles beyond traditional compliance auditing and are forging new leadership and mentoring roles as process-improvement specialists. The results have been tangible, measurable benefits for clients and the Covance organization. This article provides an overview of this cultural change and the processes put in place to improve efficiency, productivity, and customer and employee satisfaction.

Consumer Behavior↗
PubMed1998

The oncogenic T cell LIM-protein Lmo2 forms part of a DNA-binding complex specifically in immature T cells.

The LIM-only protein LMO2 is expressed aberrantly in acute T-cell leukaemias as a result of the chromosomal translocations t(11;14) (p13;q11) or t(7;11) (q35;p13). In a transgenic model of tumorigenesis by Lmo2, T-cell acute leukaemias arise after an asymptomatic phase in which an accumulation of immature CD4(-) CD8(-) double negative thymocytes occurs. Possible molecular mechanisms underlying these effects have been investigated in T cells from Lmo2 transgenic mice. Isolation of DNA-binding sites by CASTing and band shift assays demonstrates the presence of an oligomeric complex involving Lmo2 which can bind to a bipartite DNA motif comprising two E-box sequences approximately 10 bp apart, which is distinct from that found in erythroid cells. This complex occurs in T-cell tumours and it is restricted to the immature CD4(- )CD8(-) thymocyte subset in asymptomatic transgenic mice. Thus, ectopic expression of Lmo2 by transgenesis, or by chromosomal translocations in humans, may result in the aberrant protein interactions causing abnormal regulation of gene expression, resulting in a blockage of T-cell differentiation and providing precursor cells for overt tumour formation.

Adaptor Proteins, Signal Transducing↗
PubMed1998

High-energy total body irradiation as preparation for bone marrow transplantation in leukemia patients: treatment technique and related complications.

PURPOSE: Bone marrow transplantation with conditioning regimens that include total-body irradiation (TBI) is widely used in patients with acute lymphoblastic and acute myelocytic leukemias. The major causes of death in this population are relapse of leukemia, infection, and treatment related complications. Our purpose was to achieve a homogenous radiation dose distribution and to minimize the dose to the lungs, liver, and kidneys so that the incidence of organ injury was reduced. METHODS AND MATERIALS: Dose to the bone marrow, midplane, and periphery was quantified by use of thermoluminescent detectors in a bone-equivalent tissue phantom. In an effort to reduce the risk of complications, we treated relapsed or refractory leukemia patients with TBI administered in fractionated, parallel opposed large fields with 24 MV photons, using tissue compensation and partial-transmission lung shielding. Tissue toxicities were then determined. RESULTS: Dose quantitation in bone-equivalent and tissue-equivalent phantoms demonstrated that backscatter and pair production interactions adjacent to bone increased the bone marrow dose by 6 to 11%. At an SSD of 400 cm and at patient diameters of 20 to 40 cm, the percent inhomogeneity across the phantom with 24 MV photons was 0 to 0.3%, compared to 4 to 6% for 6 MV photons. End-organ toxicities consisted of clinical interstitial pneumonitis in six patients, idiopathic interstitial pneumonitis in three patients, renal toxicity in seven patients, and veno-occlusive disease of the liver in one patient. Toxicities did not correlate with fractionation schedule. CONCLUSIONS: Total-body irradiation administered with 24 MV photons increases the dose deposition in bone marrow through pair production and backscatter interactions occurring in bone. Because percent depth dose increases with SSD, the 24 MV beam is more penetrating at a 400 cm distance than at 100 cm and dose homogeneity is improved with higher energies. Thus, the incidence of radiation-mediated injury to lung, liver, and kidney is reduced. This is an effective preparatory regimen for patients with high-risk leukemias requiring bone marrow transplantation.

Adolescent↗
PubMed1998

Mortality from cancer and other causes of death among synthetic rubber workers.

OBJECTIVES: This study evaluated the mortality experience of workers from the styrene-butadiene rubber industry. Concerns about a possible association of 1,3-butadiene and styrene with lymphohaematopoietic, gastrointestinal, and lung cancers prompted the investigation. METHODS: A retrospective follow up study was conducted of 15,649 men employed for at least one year at any of eight North American styrene-butadiene rubber plants. Analyses used standardised mortality ratios (SMRs) to compare styrene-butadiene rubber workers' cause specific mortalities (1943-91) with those of the United States and Ontario general populations. RESULTS: On average, there were 25 years of follow up per subject. The standardised mortality ratio (SMR) was 87 (95% confidence interval (95% CI) 85 to 90) for all causes of death combined and was 93 (95% CI 87 to 99) for all cancers. There was an excess of leukaemia (SMR 131, 95% CI 97 to 174), restricted to hourly workers (SMR 143, 95% CI 104 to 191). For causes of death other than leukaemia, SMRs were close to or below the null value of 100. Results by work area (process group) were unremarkable for non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer. Maintenance workers had a slight increase in deaths from lung cancer, and certain subgroups of workers had more than expected deaths from cancer of the large intestine and the larynx. CONCLUSION: This study found an excess of leukaemia that is likely to be due to exposure to butadiene or to butadiene plus other chemicals. Deaths from non-Hodgkin's lymphoma, multiple myeloma, and stomach cancer did not seem to be related to occupational exposure. The excess deaths from lung cancer among maintenance workers may be due in part to confounding by smoking, which was not controlled for, and in part to an unidentified occupational exposure other than butadiene or styrene. Increases in cancer of the large intestine and larynx were based on small numbers, did not seem to be due to exposure to butadiene or styrene, and may be chance observations.

Butadienes↗
PubMed1998

Developmental patterns and gender differences in the experience of peer companionship during adolescence.

Adolescents in fifth through eighth grade (N = 218) carried electronic pagers for 1 week and completed self-report forms in response to signals received at random times. Four years later, the sample underwent the same procedure. Results indicate that thinking about the opposite sex occurs at an earlier age than spending time with the opposite sex alone and that both increase over time. Results also indicate little change in same-sex companionship over time. Girls spent more time with the opposite sex and spent more time thinking about opposite- and same-sex peers. Time with the opposite sex alone was experienced as very positive, whereas time spent thinking about the opposite sex was associated with less positive states as adolescents became older.

Adolescent↗
PubMed1997

Epidemiologic evidence on the relationship between mists containing sulfuric acid and respiratory tract cancer.

This review identified and evaluated 25 epidemiologic studies pertaining to the carcinogenicity of mists containing sulfuric acid (MSA). Few studies were designed with acid mists as the principal exposure under investigation, and in all studies exposure assessment was limited. The results of the follow-up studies from industries with high or moderate exposure potential and the case-control studies indicate, in aggregate, a moderate association between MSA and larynx cancer. The data suggest a dose-response relationship. However, many of the results from individual studies are imprecise, and confounding by smoking, alcohol, and other occupational agents is not adequately adjusted for. The biologic plausibility and the possible carcinogenic mechanism remain uncertain. There is little evidence in support of a causal relationship between exposure to MSA and lung cancer. Information is inadequate for drawing any meaningful inference about the association between exposure to MSA and nasal cancer.

Aerosols↗
PubMed1997

Chromosomal translocations and leukaemia: a role for LMO2 in T cell acute leukaemia, in transcription and in erythropoiesis.

The LMO2 gene associated with T cell acute leukaemia has been used as an example of a gene activated by association with the T cell receptor genes after chromosomal translocations. The gene is shown to encode a LIM protein which is involved in protein interactions and during normal haematopoiesis is necessary for erythroid development. LMO2 has been shown to cause tumours when aberrantly expressed and to be able to heterodimerise with TAL1 to facilitate tumour development.

Adaptor Proteins, Signal Transducing↗
PubMed1996

A follow-up study of synthetic rubber workers.

Although 1,3-butadiene (BD) has been classified as an animal carcinogen, epidemiologic research has reported inconsistent results on the relationship between BD and lymphopoietic and other cancers in humans. This study evaluated the mortality experience of 15649 men employed for at least 1 year at any of eight North American styrene-butadiene rubber (SBR) plants. About 75% of the subjects were exposed to BD; 83% were exposed to styrene (STY). During 1943-1991, the cohort had a total of 386172 and an average of 25 person-years of follow-up, with 3976 deaths observed compared to 4553 deaths expected based on general population mortality rates (standardized mortality ratio (SMR) = 87, 95% confidence interval (CI) = 85-90). More than expected leukemia deaths occurred in the overall cohort (48 observed/37 expected, SMR = 131, CI = 97-174) and among ever hourly subjects (45/32, SMR = 143, CI = 104-191). The excess was concentrated among ever hourly subjects with 10+ years worked and 20+ years since hire (28/13, SMR = 224, CI = 149-323) and among subjects in polymerization (15/6.0, SMR = 251, CI = 140-414), maintenance labor (13/4.9, SMR = 265, CI = 141-453) and laboratories (10/2.3, SMR = 431, CI = 207-793), three areas with potential for relatively high exposure to BD or STY monomers. Some cohort sub-groups had slight increases in deaths from lymphopoietic cancers other than leukemia, but mortality patterns by race, years worked and process group within the SBR industry did not indicate a causal association with occupational exposures. These results indicate that exposures in the SBR industry cause leukemia.

Butadienes↗
PubMed1996

Leukemia and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber industry.

Retrospective, quantitative estimates of exposure to 1,3-butadiene, styrene and benzene were developed for a follow-up study of leukemia mortality among 16610 subjects employed at six North American styrene-butadiene rubber manufacturing plants (418846 person-years, 58 leukemia deaths). The estimation procedure entailed identifying work areas within each manufacturing process, historical changes in exposure potential and specific tasks involving exposure, and using mathematical models to calculate job- and time-period-specific average exposures. The resulting estimates were linked with the subjects' work histories to obtain cumulative exposure estimates, which were employed in stratified and Poisson regression analyses of mortality rates. Mantel-Haenszel rate ratios adjusted by race, age, and cumulative styrene exposure increase with cumulative butadiene exposure from 1 in the nonexposed category to 4.5 in the category of 80 ppm-years or more (P = 0.01). The risk pattern is less clear and statistically nonsignificant for styrene exposure. A trend of increasing risk with butadiene exposure is still present after exclusion of the nonexposed category (P = 0.03). A parsimonious interpretation of the findings presented here, in light of previous epidemiologic studies, is that exposure to butadiene in the synthetic rubber industry produces a dose-related increase in the occurrence of leukemia.

Benzene↗
PubMed1996

The capacity to be alone as a stress buffer.

The hypothesis that the ability to comfortably spend and use time alone is a buffer against effects of stress, comparable to social support, was tested. A 20-item instrument was developed to evaluate the capacity to be alone (Winnicott, 1958) and was then administered by telephone survey to 500 U.S. adults. Findings differed for two dimensions of the capacity to be alone. Reported comfort in being alone was found to be related to lower depression, fewer physical symptoms, and greater satisfaction with life. Reported ability to use time alone to deal with stress was not related to well-being. Neither dimension showed the expected interaction with stress, and individuals with high stress who reported high solitary coping exhibited greater vulnerability on one dimension of well-being, suggesting that this coping style may reflect maladjustment.

Adaptation, Psychological↗
PubMed1996

Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) characterized by multilineage cytopenias and dysplasia but lacking an increase in blasts, with no Auer rods or monocytosis, do not exactly fit any of the categories of the French-American-British (FAB) classification of MDS and are often diagnosed as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or 'unclassifiable' MDS. It has been suggested that these 'unclassifiable' cases form a distinct subset with a clinical behavior more like that of refractory anemia with excess of blasts (RAEB) than that of RA or RARS, but few studies have been undertaken that characterize this group. We compared the clinical, hematologic, morphologic and cytogenetic features of 18 such patients - for whose disease we propose the designation 'refractory cytopenia with multilineage dysplasia' (RCMD) - to those of 42 patients meeting the FAB criteria for RA or RARS (14 patients) and RAEB (28 patients). Our results show that cytopenias in RCMD are more severe than those in RA or RARS, but are similar to those in RAEB. Erythroid hyperplasia and dyserythropoiesis are the main findings in bone marrow specimens of RA or RARS, but the major features in RCMD are multilineage proliferation and dysplasia, which, except for the lack of increased blasts resemble the findings in RAEB. Only 1/14 patients (7%) with RA or RARS had an abnormal karyotype, whereas RCMD resembled RAEB in terms of the frequency (41 vs 50%, respectively) and type of karyotypic lesions. Abnormalities of chromosomes 5 and 7 (excluding del(5q) as an isolated finding) or complex aberrations were seen only in RCMD and RAEB. in RCMD, the median survival was 24 months, with a 4-year survival rate of48 +/- 13%, intermediate between the findings in RA/RARS (107 months and 77 +/- 12%, respectively) and RAEB (18 months and 27 +/- 9%, respectively). Our data indicate that RCMD is a distinct subset of MDS, with an unfavorable clinical outcome. The designation 'refractory cytopenia with multilineage dysplasia' emphasizes the differences between such cases and the primarily dyserythropoietic, indolent subgroups of MDS, such as RA or RARS.

Adult↗
PubMed1995

Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients.

Ticlopidine is a novel antiplatelet drug reported to cause significant inhibition of several drugs metabolized by the hepatic cytochrome P-450 enzyme system, including antipyrine and theophylline. Warfarin, a racemic mixture of two enantiomers (R and S), is extensively metabolized by the CYP-450 system. S-Warfarin is five to eight times as active as R-warfarin. The effects of ticlopidine on the pharmacokinetics and pharmacodynamics of warfarin were examined in nine elderly men (69 +/- 4 years) receiving long-term warfarin therapy. Steady-state warfarin enantiomer concentrations and International Normalized Ratios (INRs) were determined at baseline and after 14 days of treatment with oral ticlopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chiral derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations (+25.7%, p < 0.05), while no significant difference in S-warfarin concentrations was noted (+0.8%). Mean INR values were not significantly different from the baseline (+8.3%), although substantial interindividual variability was noted. We conclude that ticlopidine co-medication does result in an enantioselective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients.

Aged↗
PubMed1994

The relationship of the in vivo cell cycle characteristics and treatment outcome in acute myelogenous leukemia to the expression of the FMS and MYC proto-oncogenes.

Fms expression was measured by Northern blot analysis in the pretherapy leukemia cells of 30 patients with acute myelogenous leukemia (AML) who either entered CR or who were shown to have drug resistant disease. High levels of fms expression correlated with a CR outcome and were strongly associated with the fall in the number of leukemia cells during the first six days of remission induction therapy. In contrast, similar studies of myc expression failed to demonstrate any relationship to treatment outcome. Considering those genes whose expression have been measured to date, the level of expression of fms is the one which is most highly correlated with treatment outcome in AML. No significant relationship between the expression levels of these two genes and the cell cycle characteristics of leukemia cells in vivo were detected.

Blotting, Northern↗
PubMed1993

Mitoxantrone and 5-azacytidine for refractory/relapsed ANLL or CML in blast crisis: a leukemia intergroup study.

In an effort to determine if cell cycle active agents are augmented when given after non-cell cycle active agents, 104 patients with either multiply relapsed or refractory acute nonlymphocytic leukemia or blast crisis of chronic myelogenous leukemia were treated with mitoxantrone. Patients whose bone marrow did not show significant cytoreduction received 5-azacytidine. Twenty-seven of the 93 evaluable patients (23%) with ANLL achieved a complete remission. A total of 28% of patients receiving mitoxantrone alone achieved remission compared to 15% for those receiving mitoxantrone and 5-azacytidine. Relapsed patients had a higher CR rate (36%) than refractory patients (15%). Nausea, vomiting, and stomatitis were common but rarely severe. The median duration of remission was 3.7 months and patients with abnormal karyotypes had longer remission durations than those with normal karyotypes. In this patient population, there was no evidence that 5-azacytidine given after mitoxantrone increased the complete remission rate.

Adult↗
PubMed1993

The serial study of c-myc expression in bone marrow biopsy specimens during treatment for acute myelogenous leukaemia.

The AMEX method of fixation permitted the serial study of c-myc expression in bone-marrow (BM) biopsies obtained from 6 patients with acute myelogenous leukaemia (AML) and one with myelodysplastic syndrome (MDS) during therapy with various cytotoxic and bioactive agents. BM cytotoxic therapy and therapy with bioactive agents was capable of altering c-myc expression in vivo. While cytotoxic therapy was generally associated with a fall in myc expression, it did not produce a dramatic effect on myc expression. Recombinant human granulocyte-macrophage colony-stimulating factor (RhGM-CSF) can increase and retinoic acid/alpha-interferon can decrease c-myc expression in myeloid cells in vivo.

Adult↗