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Biomedical subjects

S M Kennedy

Publications and source records attributed to S M Kennedy.

At least 37 records · Page 2Linked to original sources
PubMed1999

A new monoclonal antibody that specifically recognises the MDR-3-encoded gene product.

The MDR-3-encoded P-glycoprotein (Pgp) is highly expressed in liver and is thought to function as a hepatic transporter of phospholipids into bile. However its role, if any, in other tissues remains undefined. Although transfection experiments have indicated that it may be unable to confer drug resistance, there is evidence that it may be involved in drug resistance in certain B-cell leukaemias. To date, most work on clinical samples has been performed at the mRNA level; limited work has been performed using polyclonal antibodies raised to MDR-3 and mdr-2 (the murine equivalent of MDR-3). We have generated a new monoclonal antibody, termed 6/1G, which specifically recognises the human MDR-3 gene-encoded product. Antibody 6/1G was produced by in vitro immunisation of spleen cells from BALB/c mice with a synthetic 12-amino acid peptide. Cells from MDR-3 transgenic mice showed consistent membranous staining with antibody 6/1G. Immunoblotting with 6/1G identified a band at 170 kDa on lysates of MDR-3 transgenic cells. Preliminary results with a range of B-cell leukaemias suggest that MDR-3 Pgp positivity may be a marker for a more malignant phenotype in B-CLL. Antibody 6/1G may be useful in defining a role for MDR-3 in malignancy and drug resistance, as well as in certain liver diseases such as progressive familial intracholeostasis.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Pilomatrix carcinoma of the eyelid.

PURPOSE: To report a case of a recurring mass with an unusual origin on the eyelid of a 34-year-old man. METHOD: Case report. RESULT: Histology demonstrated that the mass was a pilomatrix carcinoma. CONCLUSION: An atypical mass with unusual symptoms or signs needs definitive treatment and diagnostic confirmation with histology.

Adult↗
PubMed1999

IL-1beta mediates diethyldithiocarbamate-induced granulocyte colony-stimulating factor production and hematopoiesis.

Diethyldithiocarbamate (DDTC) exhibits chemoprotective effects via reduced myelosuppression in mice treated with various chemotherapeutic agents. The mechanism of DDTC-mediated chemoprotection is believed to involve the induction and release of several cytokines, including interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and granulocyte colony-stimulating factor (G-CSF). In the present study the roles of IL-1beta and TNF-alpha in DDTC-mediated G-CSF induction were examined using human long-term bone marrow cultures (hLTBMCs). Administration of IL-1 receptor antagonist (IL-1ra) to DDTC-treated hLTBMCs obviated the G-CSF induction profile and blocked the resultant colony proliferation, indicating that IL-1beta mediates DDTC-induced G-CSF release and hematopoiesis. IL-1beta mRNA levels were increased threefold over control following DDTC treatment of hLTBMCs, implying that DDTC induces IL-1beta at the level of transcription. Conversely, studies involving inhibition of DDTC-induced TNF-alpha synthesis, with the inhibitor MNX 160, had no effect on DDTC-induced G-CSF release or colony proliferation. These findings taken together strongly suggest that IL-1beta mediates the chemoprotective effects of DDTC.

Adjuvants, Immunologic↗
PubMed1999

Wheat antigen content of inhalable dust in bakeries: modeling and an inter-study comparison.

The purposes of this study were (a) to compare wheat antigen content of inhalable bakery dust in Canada and the Netherlands and, (b) to evaluate the validity of dust exposure measurement as a surrogate of specific antigen exposure. Wheat antigen exposure data from the studies of Canadian and Dutch bakeries were used to explore the correlation between dust and antigen levels, and identify factors explaining variability of the antigen content of bakery dust. Direct comparison and pooling of the data were possible because the same antigen assay was used in both studies. Wheat antigen exposure samples totaling 544 were available, all originating from personal full-shift monitoring of bakery workers. The wheat antigen content of bakery dust varied greatly between the two studies and with different products within each study. Bakery dust from the Canadian study had a much higher wheat antigen content. Therefore, the interstudy difference in the wheat antigen content of bakery dust was by far the most significant in undermining the validity of the use of dust levels as a surrogate measures of wheat antigen exposure. The production of croissants, wheat bread and buns, puff pastry, bagels, and cinnamon buns was associated with increased wheat antigen content of bakery dust, while in rye bread production, bakery dust with less wheat antigen content was emitted. Although we can, in part, account for the pattern of variability in the wheat antigen content of bakery dust (explaining 49% of it), we concluded that the effort involved in modeling it accurately would probably exceed that expended in direct measurement of the antigen level. Therefore, for the exposure assessments carried out for the purpose of managing occupational risks of aeroallergen exposure in bakeries, we recommend the use of analytical techniques that can directly measure antigen exposure.

Antigens↗
PubMed1999

Homozygosity mapping and linkage analysis demonstrate that autosomal recessive congenital hereditary endothelial dystrophy (CHED) and autosomal dominant CHED are genetically distinct.

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a corneal dystrophy characterised by diffuse bilateral corneal clouding resulting in impaired vision. It is inherited in either an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form of CHED has been mapped to the pericentromeric region of chromosome 20. Another endothelial dystrophy, posterior polymorphous dystrophy (PPM), has been linked to a larger but overlapping region on chromosome 20. A large, Irish, consanguineous family with AR CHED was investigated to determine if there was linkage to this region. METHODS: The technique of linkage analysis with polymorphic microsatellite markers amplified by polymerase chain reaction (PCR) was used. In addition, a DNA pooling approach to homozygosity mapping was employed to demonstrate the efficiency of this method. RESULTS: Conventional genetic analysis in addition to a pooled DNA strategy excludes linkage of AR CHED to the AD CHED and larger PPMD loci. CONCLUSION: This demonstrates that AR CHED is genetically distinct from AD CHED and PPMD.

Chromosome Mapping↗
PubMed1999

Change in airway responsiveness among apprentices exposed to metalworking fluids.

To investigate early pulmonary responses to metalworking fluid exposure, we enrolled first-year machinist apprentices and apprentices in three other trades into a 2-yr longitudinal study. We obtained complete data for 82 machinists and 159 control subjects. Tests included respiratory questionnaires, spirometry, methacholine challenge, and allergy skin tests. Details on duration of exposure were collected by interview and 68 representative full shift personal samples for "total aerosol" were obtained from 13 shops (mean: 0.46 mg/m3, range: < 0.7 to 3.65 mg/m3). Machinists and control subjects did not differ at baseline. At follow-up, average change in bronchial responsiveness was double in machinists compared with control subjects (p = 0.05), and machinists were more likely to have developed new bronchial hyperresponsiveness (BHR) with asthmalike symptoms. In linear regression analysis, for predictors of methacholine slope, increased BHR was associated with duration of exposure to both synthetic and soluble metalworking fluids (p < 0.05); in logistic regression analysis, for predictors of BHR, only duration of exposure to synthetic fluids was a significant predictor. Results were not changed when workers with PC20 < 8 mg/ml at baseline were excluded. We conclude that exposure to water-based metalworking fluids (especially synthetic fluids) is associated with increasing BHR during the first 2 yr of exposure.

Adult↗
PubMed1999

Determinants of exposure to inhalable particulate, wood dust, resin acids, and monoterpenes in a lumber mill environment.

In a lumber mill in the northern inland region of British Columbia, Canada, we measured inhalable particulate, resin acid, and monoterpene exposures, and estimated wood dust exposures. Potential determinants of exposure were documented concurrently, including weather conditions, tree species, wood conditions, jobs, tasks, equipment used, and certain control measures. Over 220 personal samples were taken for each contaminant. Geometric mean concentrations were 0.98 mg/m3 for inhalable particulate, 0.49 mg/m3 for estimated wood dust, 8.04 micrograms/m3 for total resin acids, and 1.11 mg/m3 for total monoterpenes. Multiple regression models for all contaminants indicated that spruce and pine produced higher exposures than alpine fir or mixed tree species, cleaning up sawdust increased exposures, and personnel enclosure was an effective means of reducing exposures. Sawing wood in the primary breakdown areas of the mill was the main contributor to monoterpene exposures, so exposures were highest for the barker operator, the head rig operator, the canter operator, the board edgers, and a roving utility worker in the sawmill, and lowest in the planer mills (after kiln drying of the lumber) and yard. Cleaning up sawdust, planing kiln-dried lumber, and driving mobile equipment in the yard substantially increased exposures to both inhalable particulate and estimated wood dust. Jobs at the front end of the sawmill where primary breakdown of the logs takes place had lower exposures. Resin acid exposures followed a similar pattern, except that yard driving jobs did not increase exposures.

Air Pollutants, Occupational↗
PubMed1998

Monoclonal antibodies raised to paraffin wax embedded archival tissue; feasibility study of their potential to detect novel antigenic markers.

A study to determine the feasibility of using archival paraffin wax embedded tissue to generate monoclonal antibodies is described. Specifically, monoclonal antibodies were raised to paraffin wax embedded normal human kidney tissue to test the possibility of producing antibodies to such tissue samples prior to attempting generation of antibodies to valuable archival tissue. Multiple sections (10 x 5 microm) were pooled and dewaxed as for immunohistochemical procedures and combined with Freund's adjuvant for immunization of BALB/c mice in vivo. Immunized spleen cells were fused with SP2 myeloma cells and subsequent clones screened on paraffin wax embedded normal human kidney sections, a range of cell lines and normal mouse tissue. Supernatants from 11 wells (from a total of 90 wells screened) showed different staining patterns on sections of paraffin wax embedded kidney. One clone, 1/11C, (isotype IgG1) which exhibited strong staining on all kidney tubules by immunohistochemical studies (glomeruli interstitium and vessels were unstained) and identified a band at 52 kDa on immunoblots of dewaxed kidney tissue (as used for immunogen) was chosen for further characterization. Immunoblotting of five mammalian cell lines showed differential expression of this 52 kDa band (distinct expression on 3/5, weak expression on 2/5 cell lines) whereas, all cell lines displayed a band at 44 kDa and a third band at 70 kDa was observed on 2/5 cell lines. In mouse tissue extracts, the 52 kDa band was identified in kidney tissue only (not in the lung, liver or spleen) with the 44 kDa and 70 kDa bands weakly expressed in all tissues. This preliminary investigation of a novel approach to identifying possible new antigenic markers or producing monoclonal antibodies which react better to known antigens on sections of paraffin wax embedded tissue showed that this method is feasible. The need to have a comprehensive screening system in place and the ability to identify potentially useful clones after the initial screening is paramount due to the relative scarcity of screening material (archival tissue sections) and the tedious nature of the screening method.

Animals↗
PubMed1998

Cytogenetic analysis of South Asian berry pickers in British Columbia using the micronucleus assay in peripheral lymphocytes.

Micronuclei in peripheral blood lymphocytes from British Columbia seasonal farmworkers and controls were evaluated using the cytokinesis-block technique. The farmworkers harvested berry crops and were likely occupationally exposed to pesticides. Subjects were 39 female subjects of South Asian descent; 18 farmworkers employed during 1993 and 21 age-matched controls. The mean age was 55.9 years. Micronuceli were also scored for the presence of kinetochores. No significant difference was found between the frequency of micronucleated binucleates in the farmworkers group (19.20/1000 binucleates), and the control group (21.76/1000 binucleates). However, among the farmworkers employed in 1993, there was a positive, but not statistically significant, association between micronucleated cell frequency and weeks worked: 16.44/1000 binucleates in those working less than 20 weeks; 23.78/1000 binucleates in those working 20 to 23 weeks; and 25.43/1000 binucleates in those working more than 23 weeks. In those who had ever been employed as farmworkers, there was an elevated frequency of micronucleated cells in the group with the longest history of employment as a farmworker (25.28/1000 binucleates) compared to those with the shortest employment history (16.48/1000 binucleates). This trend remained evident after adjusting for age, red blood cell folate, meat consumption, coffee consumption and recent vaccination. A positive association between the consumption of meat and micronucleus frequency was also observed. Non-meat eaters were likely life-long vegetarians. Micronuclei in farmworkers had a lower frequency of kinetochore positive micronuclei than controls. This study indicates that South Asian berry pickers in British Columbia may be at risk for genetic damage. More studies in other ethnic groups and in males are needed to generalize the findings of this study. More direct measures of exposure are needed to elucidate the sources of genotoxicity.

Adult↗
PubMed1998

Conjunctival 'MALToma' with systemic recurrence.

We report the recurrence of a localized conjunctival lymphoma arising in mucosal-associated lymphoid tissue (MALToma) in the psoas muscle, 18 months after initial treatment with radiotherapy. Findings from systemic investigations demonstrated MALToma recurrences in the psoas muscle and the stomach. Ocular adnexal MALTomas typically manifest as localized tumors, which respond well to radiotherapy, but a proportion may recur in typical MALT sites. To our knowledge, this is the first report of a recurrence in the psoas muscle, and the clinical implication is that all patients with ocular adnexal lymphomas need to be followed up for an indefinite period.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

MDR1 expression is associated with adverse survival in melanoma of the uveal tract.

Metastatic uveal melanoma is profoundly chemoresistant and has a very poor outcome. We have previously shown that the MDR1 gene and its gene product P-glycoprotein (P-gp), which are known to cause drug resistance in cancer cells, are expressed in ocular melanoma. Overexpression of MDR1 has been associated with a poor survival in some tumor types treated by chemotherapy and in some untreated tumours. To assess whether MDR1 expression is of prognostic value in uveal melanoma, we evaluated the expression of MDR1 by immunohistochemistry in 108 cases. Three semiquantitative grades were used to evaluate positive staining. We detected MDR1 expression in 80% of cases; 28% showed grade I staining; 30%, grade II staining; and 22%, grade III staining. There was a statistically significant association (P=.004) between MDR1 expression by tumor cells and shorter survival times (n=96), which was most striking at grade III levels of expression. Multivariate analysis showed that MDR1 expression is an independent prognostic indicator of poor survival. We conclude that (1) MDR1 may be involved in chemoresistance and tumor propagation in primary uveal melanoma, and (2) increasing levels of expression are prognostically significant and may prove a useful marker of tumor invasiveness, independent of established prognostic factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Determinants of wheat antigen and fungal alpha-amylase exposure in bakeries.

The study's objectives were to measure flour antigen exposure in bakeries and define the determinants of exposure. Ninety-six bakery workers, employed in seven different bakeries, participated in the study. Two side-by-side full-shift inhalable dust samples were obtained from each study participant on a single occasion. The flour antigen exposure was measured as wheat antigen and fungal alpha-amylase content of the water-soluble fraction of inhalable dust, assayed via enzyme-linked immunosorbent assays. During the entire sampling period bakers were observed and information on 14 different tasks was recorded at 15-minute intervals. Other production characteristics were also recorded for each sampling day and used in statistical modeling to identify significant predictors of exposure. The mean alpha-amylase antigen exposure was 22.0 ng/m3 (ranging from below the limit of detection of 0.1 ng/m3 to 307.1 ng/m3) and the mean wheat antigen exposure was 109 micrograms/m3 (ranging from below the limit of detection of 1 microgram/m3 to 1018 micrograms/m3). Regression models that explained 74% of variability in wheat antigen and alpha-amylase antigen exposures were constructed. The models indicated that tasks such as weighing, pouring, and operating dough-brakers increased flour antigen exposure, while packing and decorating resulted in lower exposures. Croissant, puff-pastry, and bread/bun production lines were associated with increased exposure, while cake production and substitution of dusting with the use of divider oil were associated with decreased exposure. Exposure levels can be reduced by the automation of forming tasks, alteration of tasks requiring pouring of flour, and changes to the types of products manufactured.

Air Pollutants, Occupational↗
PubMed1997

Assessment of chromosome 3 copy number in ocular melanoma using fluorescence in situ hybridization.

Recent reports have indicated that monosomy 3 is a marker of poor prognosis in uveal melanoma. Fluorescence in situ hybridization (FISH) was performed on fresh touch preparations from 17 uveal, and 5 conjunctival melanomas, using the chromosome 3 centromeric probe, D3Z1. Of the 17 uveal melanomas, all of which originated in the choroid, two cases revealed a monosomy of chromosome 3. One of the conjunctival melanomas contained a major clone that was trisomic for chromosome 3, and another conjunctival melanoma contained a tetrasomic population. FISH, using the alpha-satellite probe for chromosome 3 on uveal melanoma imprints, allows one to predict which patients are potentially at a higher risk of relapse. Multiplication, rather than deletion, of copies of chromosome 3 in conjunctival melanomas may be a nonspecific aberration, perhaps indicative of polyploidy, a characteristic of tumor progression.

Adult↗
PubMed1997

What to do about softwood? A review of respiratory effects and recommendations regarding exposure limits.

Wood dust has been classified as a human carcinogen by the International Agency for Research on Cancer with a footnote that the evaluation was based on a marked excess of sino-nasal cancer among workers exposed primarily to hardwood dusts. Because the epidemiologic data on the carcinogenic effects of softwoods are weaker than for hardwoods, standard setting for softwood dust presents a greater dilemma. Unfortunately, the studies of wood dust and cancer do not have the quantitative exposure data necessary for standard setting for either hardwoods or softwoods. Asthma, non-asthmatic airflow obstruction, and both upper and lower respiratory symptoms have been associated with exposure to both 'allergenic' and 'non-allergenic' softwood dusts, and an association with increasing intensity of exposure has been observed in multiple studies. The available evidence seems to indicate that to prevent these nonmalignant effects, the level of exposure to all softwood dust should be at least as low 2 mg/m3. A standard of 1 mg/m3 may be more appropriate to provide a safety margin to protect more sensitive workers. It may be that some of the health effects observed are due to the natural components of wood, such as resin acids or monoterpenes, or to molds.

Air Pollutants, Occupational↗
PubMed1997

Respiratory health of automobile workers exposed to metal-working fluid aerosols: respiratory symptoms.

A total of 1,811 automobile workers at three General Motors facilities were evaluated by questionnaire for possible respiratory effects resulting from airborne exposures to metal-working fluids (MWF): 1,042 currently worked as machinists and were exposed to one of three types of MWF aerosols (straight mineral oils, soluble oil emulsions, or water-based synthetic fluids that contained no oils); 769 assembly workers, without direct exposure, served as an internal reference group (of these, 239 had never worked as machinists). Symptoms of usual cough, usual phlegm, wheezing, chest tightness, and breathlessness, as well as physician-diagnosed asthma, and chronic bronchitis were the primary outcomes examined. Machinists as a whole had higher prevalence of cough, phlegm, wheezing, and breathlessness than that of assembly workers. Adjusting for confounding, phlegm and wheeze were associated with increasing levels of current exposure to straight oils; cough, phlegm, wheeze, chest tightness, and chronic bronchitis were associated with increasing levels of current exposure to synthetics. In models that included both past and current exposure, only current exposures to straight and synthetic fluids were associated with current symptoms.

Aerosols↗
PubMed1997

Exposure levels and determinants of inhalable dust exposure in bakeries.

The study's objectives were to measure full-shift exposure to inhalable dust in bakeries and define the determinants of full-shift exposure. Inhalable dust was measured gravimetrically. Ninety-six bakery workers, employed in seven different bakeries, participated in the study. Two side-by-side full-shift inhalable dust samples were obtained from each study participant on a single occasion. Samples were collected on 18 days selected at random. During the entire sampling period, bakers were observed and information on 14 different tasks was recorded at 15 min intervals. Other production characteristics were also recorded for each sampling day. These task and production variables were used in statistical modelling to identify significant predictors of exposure. The mean full-shift inhalable dust exposure was 8.2 mg/m3 (range: 0.1-110 mg/m3). A regression model explained 79% of the variability in exposure. The model indicated that tasks such as weighing, pouring and operating dough-brakers and reversible sheeters increased the exposure, while packing, catching and decorating decreased the exposure. Bread and bun production lines were associated with increased full-shift inhalable dust exposure, while cake production and substitution of dusting with the use of divider oil were associated with decreased exposure. Production tasks and characteristics are strong predictors of personal full-shift exposures to flour dust among bakers; these can be altered to reduce exposure levels.

Analysis of Variance↗