ABSTRACT
OBJECTIVES: It has consistently been shown that women who are diagnosed with bladder cancer have lower survival than men, but the exact mechanism remains unknown. Most studies assumed that the sex-specific mortality ratio is constant over time, possibly resulting in inaccurate estimates in various periods of follow-up. This study aimed to investigate the sex-specific excess mortality in bladder cancer patients and its variation over follow-up time. METHODS: Observational cohort study. Using data from the population-based Netherlands Cancer Registry, we studied 24,169 patients diagnosed between 2003 and 2014 with histologically confirmed ≥T1 bladder cancer with follow-up until January 2018. We used flexible parametric relative survival models to estimate excess mortality as a function of time for each sex and to explore the effect of covariates on these functions. RESULTS: Female patients (24%) had worse clinical tumor, node, and metastasis-stage at diagnosis and more often a nonurothelial tumor histology. The excess mortality ratio of sex was not constant over time; in the first two years after diagnosis excess mortality rates for women were higher than for men, but lower thereafter; this applied to both nonmuscle-invasive and muscle-invasive bladder cancer subgroups. Baseline differences in age, tumor, node, and metastasis-stage and histology accounted for only part of the excess mortality gap. CONCLUSIONS: The assumption of proportional hazards over time leads to underestimation of the excess mortality ratio for women in the first two years and overestimation thereafter, when excess mortality is comparable for women and men. Clinicians should incorporate the initial sex-specific poorer outcome in their considerations regarding prognosis and treatment options for female patients, e.g., more invasive treatment and neo-adjuvant treatment. These findings also point towards a mechanism of micrometastatic disease, warranting assessment of sex-specific efficacy in randomized controlled trials on treatments in this patient population.
Subject(s)
Urinary Bladder Neoplasms/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Cohort Studies , Cystectomy , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Netherlands/epidemiology , Prognosis , Registries/statistics & numerical data , Risk Factors , Sex Factors , Survival Rate , Time Factors , Urinary Bladder/pathology , Urinary Bladder/surgery , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/therapy , Young AdultABSTRACT
BACKGROUND: A redesigning of primary care is required to meet dementia patients' needs. In the Netherlands, current dementia care still falls short in areas including ad hoc collaboration, lack of feedback on quality to professionals involved, and insufficient implementation of established multidisciplinary guidelines. OBJECTIVE: DementiaNet is a collaborative care approach, which aims to reduce the burden of the disease on individuals, healthcare services and society via network-based care that encourages collaboration, enhances knowledge and skills and stimulates quality improvement cycles. MATERIAL AND METHODS: DementiaNet was developed to support primary care networks through implementation of five core processes: network-based care, clinical leadership, quality improvement cycles, interprofessional practice-based training and communication support tools, following a stepwise tailor-made approach. Alongside this, a mixed method study was designed to evaluate innovation and effectiveness. RESULTS: Currently, 18 networks have been formed. These vary in quality of care and strength of collaboration due to local circumstances. Initial activities and goals of each network also vary, ranging from acquaintance to shared care plans. Ongoing research will identify barriers, facilitators and merits of the approach in increasing quality of care and ultimately improving outcomes for patient, carer, health service and society. CONCLUSION: Initial results show that clinical practice varies and the DementiaNet approach can lead to quality improvement. Complexity and variety of local care requires complex interventions and evaluation methods that account for this in order to safeguard the value for practice. Strict methodology lessens external validity.
Subject(s)
Dementia/diagnosis , Dementia/therapy , Organizational Objectives , Patient Care Management/organization & administration , Patient Care Team/organization & administration , Primary Health Care/organization & administration , Quality Improvement/organization & administration , Aged , Aged, 80 and over , Europe , Female , Humans , Interprofessional Relations , Male , Models, Organizational , Netherlands , Physicians, Primary Care/education , Physicians, Primary Care/organization & administration , United StatesABSTRACT
A cohort of 439 haematopoietic SCT recipients was analysed to determine the incidence of Gram-positive coccal bacteraemia and thromboembolic events associated with the use of central venous catheters (CVCs) and to determine risk factors for these complications. The incidences of persistent coagulase-negative staphylococcal (CoNS) bacteraemia, symptomatic thrombosis and thrombophlebitis were 25%, 9.6% and 6.6%, respectively. Duration of neutropenia (in days, odds ratio (OR) 1.02; P=0.04) and left-sided placement of the CVCs (OR 1.73; P=0.03) were independent risk factors for the occurrence of persistent CoNS bacteraemia, whereas the use of less mucotoxic conditioning regimens was associated with a lower risk (high-dose melphalan (HDM)/BEAM vs other regimens, OR 0.24; P<0.001). Use of TBI, persistent CoNS bacteraemia and tip colonisation were all significantly associated with an increased risk of symptomatic thrombosis (OR 6.03, 3.36 and 2.80, respectively; Pîº0.02). The risk factors found in this cohort of SCT recipients differed from those found in the general cancer population, showing an important role for persisting bacteraemia in the pathogenesis of CVC-associated thrombosis. Therefore, we constructed a new algorithm in order to improve catheter management and prevent these CVC-related complications.
Subject(s)
Bacteremia/etiology , Gram-Positive Bacteria/pathogenicity , Hematopoietic Stem Cell Transplantation/adverse effects , Thrombosis/etiology , Transplantation Conditioning/adverse effects , Adolescent , Adult , Aged , Catheterization, Central Venous/adverse effects , Cohort Studies , Female , Humans , Incidence , Male , Middle Aged , Risk Factors , Young AdultABSTRACT
Semiquantitative measurements of chronic inflammation of the centriacinar region (proximal acinus of lung) were compared between 20 Miami and 18 Los Angeles residents (ages 11-30 years) for whom smoking histories were available. Mean extent and severity scores of four lung sites were higher for Los Angeles than Miami residents, with effect of city statistically significant for extent (P=0.02). Also, maximum scores for extent and severity by city were significantly greater for Los Angeles residents (P=0.02, each), but not by smoking history. Smokers did have higher scores for mean extent and severity (by lung site and smoking history), but neither this nor inclusion of smoking and city in the model reached significance. With respect to maximum extent and maximum severity scores, a stratified comparison of cities by smoking history showed a trend (not significant) toward higher scores for Los Angeles residents. Mean extent and severity scores for the lower lobe were higher for basilar sections than for apical sections (each P<0.001). Cumulative data indicate that expanded pathologic studies are essential for efforts to complete a convergence of epidemiological and experimental data implicating exceedences of the Federal ozone standard as a contributor to human lung injury.
Subject(s)
Lung/pathology , Adolescent , Adult , Air Pollutants/toxicity , Child , Chronic Disease , Humans , Inflammation/pathology , Ozone/toxicity , SmokingABSTRACT
This article reports on an ongoing exploratory study of the quality of obstetrical and gynaecological care for an ethnic pluriform patient population in two non-academic city hospitals in the Netherlands. A bird's eye view is given of the study's background, goals and methodology, followed by a few preliminary results and by some concluding remarks about the need to pay more attention to cultural diversity in health care.
Subject(s)
Ethnicity , Maternal Health Services/standards , Quality of Health Care , Cultural Diversity , Emigration and Immigration , Female , Health Services Research , Hospitals, Urban , Humans , Maternal Health Services/statistics & numerical data , NetherlandsABSTRACT
This study presents a promising selection system for gene-modified cells other than human hematopoietic progenitor and endothelial cells based on transgenic expression of human CD34. Three retrovirally transduced variants of CD34 were compared, differing in the length of their cytoplasmic domains. These were the full-length transmembrane protein (flCD34), a truncated form (tCD34) that is found as a naturally occurring splice variant and has a partial deletion of the cytoplasmic domain for signal transduction, and an engineered variant which is completely deprived of its cytoplasmic tail (dCD34). All three variants allowed selection of gene-modified cells using commercially available immunoaffinity technology. However, examination by flow cytometry as well as by Southern, Northern, and Western blot revealed that dCD34, as opposed to tCD34, is not stably anchored in the membrane and thus is expressed at low levels on the surface of transduced cells. Therefore, tCD34 was chosen as the more promising candidate for a clinically applicable cell surface marker. We show that gene-modified human primary T lymphocytes expressing tCD34 can be enriched to high purity (>95%) using clinically approved immunoaffinity columns. In addition, we demonstrate the utility of tCD34 for surface marking of murine hematopoietic cells in vivo, including primary T lymphocytes detected 9 weeks after bone marrow transplantation.
Subject(s)
Antigens, CD34/genetics , Antigens, Surface/genetics , DNA, Recombinant , Gene Expression , Retroviridae/genetics , T-Lymphocytes/metabolism , Animals , Antigens, CD34/biosynthesis , Antigens, Surface/biosynthesis , Blotting, Western , Bone Marrow/metabolism , Bone Marrow/virology , Cell Separation/methods , DNA/analysis , DNA Primers/chemistry , Flow Cytometry , Genetic Vectors , Humans , Immunomagnetic Separation , Jurkat Cells , Mice , Mice, Inbred C57BL , Nucleotide Mapping , Retroviridae/metabolism , T-Lymphocytes/cytology , TransfectionABSTRACT
Circulating cholesterol oxidation products (ChOx) have long been implicated in the etiology of early atherosclerosis; however, direct in vivo evidence elucidating their role in atherogenesis is only recently becoming available. This study investigated ChOx effects on vascular lesion formation in New Zealand White rabbits under controlled hypercholesterolemic conditions. By closely monitoring plasma cholesterol levels and adjusting dietary cholesterol intake during a 78-day period, total plasma cholesterol exposures (cumulative plasma cholesterol levels over time) were controlled between 27 000 and 34 000 mg/dLxday (final plasma cholesterol concentration, 467+/-77 mg/mL), representing a threshold range for sudanophilic lesion formation in the aorta. Twenty injections of a ChOx mixture (70 mg per injection) were made bearing an oxysterol composition similar to that found in circulating oxidatively modified low density lipoprotein. At sacrifice, the ChOx-injected rabbits (n=5) had (1) significantly higher plasma ChOx levels, (2) significantly increased cholesterol content in the aortas, mainly as esterified cholesterol, and (3) significantly greater sudanophilic lesion size and frequency in the aortas compared with vehicle-injected control rabbits (n=5). The aortic cholesterol content and extent of sudanophilic lesion area were correlated significantly with total plasma ChOx exposure (P<0.003 and P<0.0001, respectively) but not with total cholesterol exposure. The results indicate that for moderate experimental hypercholesterolemia, a situation more relevant to physiological hypercholesterolemia in humans, circulating ChOx may play an important role in inducing formation of early atherosclerotic lesions. Because ChOx are often present in cholesterol-containing diets, foam cell lesion formation induced by ChOx rather than cholesterol cannot be overlooked.
Subject(s)
Aorta/metabolism , Aorta/pathology , Cholesterol/metabolism , Foam Cells/pathology , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Animals , Azo Compounds , Cholesterol/blood , Cholesterol Esters/metabolism , Chylomicrons/blood , Coloring Agents , Hypercholesterolemia/blood , Liver/metabolism , Male , Oxidation-Reduction , RabbitsABSTRACT
PURPOSE: Previous studies have shown that ovariectomy and hypophysectomy cause regression of the lacrimal gland and have implicated androgens as trophic hormones that support the gland. The purposes of this study were to test the hypothesis that glandular regression after ovariectomy is due to apoptosis, to identify the cell type or types that undergo apoptosis, to survey the time course of the apoptosis, and to determine whether ovariectomy-induced apoptosis could be prevented by dihydrotestosterone (DHT) treatment. METHODS: Groups of sexually mature female New Zealand White rabbits were ovariectomized and killed at various time periods up to 9 days. Additional groups of ovariectomized rabbits were treated with 4 mg/kg DHT per day. At each time period, sham-operated rabbits were used as controls. Lacrimal glands were removed and processed for analysis of apoptosis as assessed by DNA fragmentation and for morphologic examination. DNA fragmentation was determined using the TdT-dUTP terminal nick-end labeling assay and by agarose gel electrophoresis. Labeled nuclei were quantified by automated densitometry. Sections were also stained for RTLA (rabbit thymic lymphocyte antigen), rabbit CD18, and La antigen. Morphology was evaluated by both light and electron microscopy. RESULTS: The time course of apoptosis exhibited two phases, a rapid and transient phase and a second prolonged phase. A transient phase peaked at approximately 4 to 6 hours after ovariectomy. The values for degraded DNA as a percentage of total nuclear area were 4.29%+/-0.79% and 4.26%+/-0.54%, respectively. The values for sham-operated controls examined at the same time periods were 1.77%+/-0.08% and 0.82%+/-0.21%, respectively. The percentage of degraded DNA at 24 hours after ovariectomy was not different from controls examined at the same interval after sham operation. The percentage of degraded DNA 6 days after ovariectomy was significantly increased (8.5%+/-2.4%), compared with sham-operated animals at the same time period (0.68%+/-0.03%). DNA laddering was more pronounced after ovariectomy. Dihydrotestosterone treatment in ovariectomized rabbits suppressed the increase in DNA degradation. Morphologic examination of lacrimal gland sections indicated that ovariectomy caused apoptosis of interstitial cells rather than acinar or ductal epithelial cells. Tissue taken 4 hours and 6 days after ovariectomy showed nuclear chromatin condensation principally in plasma cells. Increased numbers of macrophages were also evident. Significant levels of cell degeneration and cell debris, characteristic of necrosis, were observed in acinar regions 6 days after ovariectomy. Dihydrotestosterone prevented this necrosis. Increased numbers of RTLA+, CD18+, and La+ interstitial cells were also evident 6 days after ovariectomy. In addition, ovariectomy increased La expression in ductal cells. Dihydrotestosterone treatment prevented the increase in numbers of lymphoid cells and La expression. Dihydrotestosterone also promoted the appearance of mitotic figures in acinar cells and increased the sizes of acini by 43% (P < 0.05). CONCLUSIONS: Glandular atrophy observed after ovariectomy is likely to proceed by necrosis of acinar cells rather than apoptosis. This process begins with an apparent time lag after a rapid phase of interstitial cell apoptosis. These processes are accompanied by increased lymphocytic infiltration. These results suggest that a critical level of androgen is necessary to maintain lacrimal gland structure and function and that a decrease in available androgen below this level could trigger lacrimal gland apoptosis and necrosis, and an autoimmune response. Because apoptotic and necrotic cell fragments may be sources of autoantigens that can be processed and presented to initiate an autoimmune reaction, we surmise that cell death triggered by androgen withdrawal may trigger an autoimmune response such as that encountered in Sjögren's syndrome. (ABSTRACT TRUNCATED)
Subject(s)
Apoptosis/drug effects , Chemotaxis, Leukocyte/physiology , Dihydrotestosterone/pharmacology , Lacrimal Apparatus/pathology , Lymphocytes/physiology , Animals , Autoantigens/metabolism , CD18 Antigens/metabolism , DNA/analysis , DNA Fragmentation , Electrophoresis, Agar Gel , Female , Immunoenzyme Techniques , In Situ Nick-End Labeling , Lacrimal Apparatus/drug effects , Lacrimal Apparatus/ultrastructure , Necrosis , Ovariectomy , Rabbits , Ribonucleoproteins/metabolism , SS-B AntigenABSTRACT
Gene transfer vectors based on simple retroviruses and more complex lentiviruses are currently the most reliable tools for stable establishment of transgenes in hematopoietic cells. While important hurdles in basic gene transfer technologies have been overcome in recent years, there is still some uncertainty in the choice of the cis-regulatory elements of the vector. These elements dictate the overall level, clonal variability, response to differentiation and persistence of transgene expression in vivo and thus have a significant influence on the outcome of therapeutic applications of somatic gene transfer. The rationale underlying the further improvement of such cis-elements is reviewed here.
Subject(s)
Bone Marrow Cells/metabolism , Genetic Vectors , Retroviridae/genetics , Animals , Gene Expression , Gene Transfer Techniques , Genetic Therapy/methods , Humans , RNA Processing, Post-TranscriptionalABSTRACT
A study of 161 Los Angeles County residents aged 12-28 years old who had died sudden violent deaths showed frequent and severe chronic glandular bronchitis (CGB), that is to say grade > or =5 (0-10) chronic inflammation involving at least one, half or more, and all submucosal glands in 53.4%, 21%, and 4.4% of the main stem bronchi, respectively. The mean plasma cell/gland/bronchus was high (> or =5) for 22 subjects (13.7%), while only 2 bronchi (1.2%) had a correspondingly high lymphocyte mean (P<0.001). Of the bronchi, 75.2% were affected by glandular atrophy (> or =5 in 8.1%), 10.6% had neutrophil infiltration of glands, and 3.1% had acute sialadenitis. Of the total of 1040 glands, CGB was found in 83.8% (> or =5 in 26.5%). Of 25 non-smokers identified, 14 (56%) had some degree of CGB in > or =50% of the glands, severe in 7 (26%). Severe CGB in many young individuals raises concern that a subpopulation of living cohorts may have an increased susceptibility to disease and a rising incidence of chronic lung disease. Demographic analysis is pending, but respiratory infection, smoking, adverse socioeconomic factors, and air pollution are all potential causative factors. Since pollution in Los Angeles frequently exceeds air quality standards, an ongoing multicity study is attempting to distinguish between the suspected effects of air pollution and confounding variables.
Subject(s)
Bronchitis/epidemiology , Adolescent , Adult , Atrophy/pathology , Bronchi/pathology , Bronchitis/pathology , Child , Chronic Disease , Female , Fibrosis/pathology , Humans , Incidence , Los Angeles/epidemiology , Lymphocytes/pathology , Male , Mucous Membrane/pathology , Plasma Cells/pathology , Urban PopulationABSTRACT
The polycythemic strain of the Friend spleen focus-forming virus (SFFVp) is a replication-defective, acutely transforming retrovirus inducing a bistage erythroleukemia in susceptible mice. The first stage of the disease is an acute polyclonal erythroblastosis induced by the proliferation-promoting effect of gp55. gp55 is expressed from a spliced subgenomic message of SFFVp and stimulates the cellular receptor for erythropoietin. Using a selectable SFFVp that otherwise mimics the specificity of the disease, we demonstrate that the kinetics of the polyclonal expansion depends on the transcriptional strength of the retroviral cis-active elements. By exchanging gp55 for apathogenic genes, we show that SFFVp enhancer and splice signals can be successfully utilized for the development of retroviral vectors mediating very efficient transgene expression in hematopoietic cells. Apathogenic selectable SFFVp-based vectors carrying distinct enhancer alterations are a valuable tool to analyze transcriptional control of leukemia viruses in the absence of oncogenic proteins. Moreover they might have therapeutic potential.
Subject(s)
Erythropoiesis , Friend murine leukemia virus/genetics , Leukemia, Experimental/genetics , RNA, Viral/genetics , Spleen Focus-Forming Viruses/genetics , Tumor Virus Infections/genetics , Animals , Enhancer Elements, Genetic , Gene Expression Regulation, Viral , Genetic Vectors , Humans , Leukemia, Erythroblastic, Acute/virology , Leukemia, Experimental/physiopathology , Leukemia, Experimental/prevention & control , Mice , RNA Splicing , Rats , Repetitive Sequences, Nucleic Acid , Retroviridae Infections/genetics , Transduction, GeneticABSTRACT
To identify determinants that form nonapeptide hormone binding domains of the white sucker Catostomus commersoni [Arg8]vasotocin receptor, chimeric constructs encoding parts of the vasotocin receptor and parts of the isotocin receptor have been analyzed by [(3,5-3H)Tyr2, Arg8]vasotocin binding to membranes of human embryonic kidney cells previously transfected with the different cDNA constructs and by functional expression studies in Xenopus laevis oocytes injected with mutant cRNAs. The results indicate that the N terminus and a region spanning the second extracellular loop and its flanking transmembrane segments, which contains a number of amino acid residues that are conserved throughout the nonapeptide receptor family, contribute to the affinity of the receptor for its ligand. Nonapeptide selectivity, however, is mainly defined by transmembrane region VI and the third extracellular loop. These results are complemented by a molecular model of the vasotocin receptor obtained by aligning its sequence with those of other G-protein coupled receptors as well as that of bacteriorhodopsin. The model indicates that amino acid residues of transmembrane regions II-VII that are located close to the extracellular surface also contribute to the binding of vasotocin.
Subject(s)
Protein Structure, Secondary , Receptors, Vasopressin/chemistry , Receptors, Vasopressin/metabolism , Vasotocin/metabolism , Amino Acid Sequence , Animals , Binding Sites , Cell Line , Cell Membrane/metabolism , DNA Mutational Analysis , Female , Fishes , Humans , Kidney , Kinetics , Models, Molecular , Models, Structural , Molecular Sequence Data , Mutagenesis, Site-Directed , Oocytes/physiology , Polymerase Chain Reaction , Rats , Receptors, Vasopressin/biosynthesis , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , Sequence Homology, Amino Acid , Transfection , Tritium/metabolism , Xenopus laevisABSTRACT
Alveolar macrophages (AM) have been found to suffer significant functional deficits in response to nitrogen dioxide (NO2) exposure. The present investigation examined changes in the activation of AM arachidonate metabolism and superoxide production in response to an environmentally relevant level of NO2. Rats were exposed to 0.5 ppm NO2 for periods of 0.5-10 d and AM were obtained by bronchoalveolar lavage (BAL). NO2 exposure produced complex effects upon both unstimulated and stimulated AM arachidonate metabolism. Unstimulated AM synthesis of leukotriene B4 (LTB4) was depressed rapidly within 1 d of exposure, and depressed again at 5 d. Alveolar macrophage production of thromboxane B2 (TxB2), LTB4, and 5-hydroxyeicosatetraenoate (5-HETE) in response to stimulation with the calcium ionophore, A23187, were acutely depressed within 1 d of exposure; however, generation of these compounds recovered to air-control levels with longer exposure, while 5-HETE was increased at 10 d. In contrast, AM production of LTB4 in response to another stimulus, zymosan-activated rat serum (ZAS), was not depressed until following 5 d of exposure and remained slightly lower than air-control levels at 10 d. Levels of TxB2, LTB4, prostaglandin E2 (PGE2), and prostaglandin F2 alpha (PGF2 alpha) measured in BAL fluid (BALF) were found to be depressed within 4 h of exposure, suggesting an acute decrease in the in vivo pulmonary arachidonate metabolism; however, production of these compounds generally recovered to air-control levels with longer exposure. The AM superoxide production stimulated by phorbol myristate acetate (PMA) was decreased rapidly and continuously throughout the study. Thus, exposure to a low concentration of NO2 acutely depresses activation of AM arachidonate metabolism and superoxide production in response to external stimuli, and may impede defense against pulmonary infection.
Subject(s)
Arachidonic Acids/metabolism , Macrophages, Alveolar/drug effects , Nitrogen Dioxide/toxicity , Superoxides/metabolism , Animals , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Dinoprost/metabolism , Dinoprostone/metabolism , Glutathione/metabolism , Hydroxyeicosatetraenoic Acids/metabolism , Leukotriene B4/metabolism , Macrophages, Alveolar/metabolism , Male , Oxidation-Reduction , Rats , Rats, Sprague-Dawley , Respiratory Burst , Specific Pathogen-Free Organisms , Thromboxane B2/metabolismABSTRACT
The effects of ozone on thymocyte and spleen T lymphocyte subpopulations were studied. Balb/c mice were exposed to clean air or to 0.3 +/- 0.05 ppm ozone for 1-3 wk. Thymocytes and spleen T cells were stained with fluorochrome conjugated monoclonal antibodies against surface differentiation markers and/or propidium iodide for deoxyribonucleic acid (DNA). The cells were then analyzed by fluorescence activated cell sorter. The percentages of certain thymocyte and spleen T lymphocyte subtypes and DNA synthesizing spleen T cells were lower following 1 wk of ozone exposure. After 3 wk exposure, the thymocyte percentages were higher in ozone-exposed mice, whereas the absolute number remained lower, and spleen T lymphocytes showed no changes. The findings suggest that short-term ozone inhalation can affect the T cell immune system adversely, particularly the CD4+ cells.
Subject(s)
Ozone/toxicity , Spleen/drug effects , T-Lymphocytes/drug effects , Thymus Gland/drug effects , Animals , Atmosphere Exposure Chambers , CD4 Antigens/drug effects , CD4 Antigens/immunology , Female , Flow Cytometry , Mice , Mice, Inbred BALB C , Ozone/immunology , Spleen/immunology , Thymus Gland/immunologyABSTRACT
The effects of exposure to an ambient level of nitrogen dioxide (NO2) on the development and progression of the spontaneous T-cell lymphoma in AKR/cum mice are evaluated. The animals were exposed to 0.25 ppm +/- 0.05 ppm NO2 for 7 hr/day, 5 days/week for up to 181 days. Following exposure periods of 37, 71, 111, 141, and 181 days, the extent of lymphoma was determined microscopically in histologic sections of the thymus, spleen, lymph nodes, lung, and liver. In addition, T-lymphocyte subpopulations were quantitated by flow cytometry. The results indicate that the development and progression of lymphoma in mice was influenced by intermittent inhalation of NO2. The lymphoma was detectable earlier in control animals and the survival of the NO2-exposed group was significantly higher. The T-lymphocyte subpopulations were significantly lower in NO2-exposed animals following 37 and 181 days of NO2 exposure. The T-helper/inducer (CD4+) lymphocytes were adversely affected to the greatest extent, explaining in part the more aggressive behavior of the lymphoma in the control animals. Most importantly, these studies provide additional evidence that in vivo exposure to a level of NO2 commonly encountered in polluted metropolitan areas adversely affects cells of the immune system. In the case of the AKR mouse, the adverse effect of NO2 on CD4+ cells manifested itself by retarding development and progression of the spontaneous lymphoma. Our data suggest that this neoplasm may be dependent on growth factors such as interleukin 2, produced by CD4+ lymphocytes in the early stages.
Subject(s)
Lymphoma/pathology , Nitrogen Dioxide/pharmacology , Air Pollutants , Animals , Flow Cytometry , Immunity, Cellular , Lymphoma/immunology , Mice , Mice, Inbred AKR , Spleen/pathology , Survival Analysis , T-Lymphocyte Subsets/pathologyABSTRACT
The effect of acute exposure to nitrogen dioxide (NO2) on splenic T lymphocyte subpopulations was studied in C57BL/6cum mice. The mice were exposed to 4 ppm NO2 for 8 hr. Monoclonal antibodies to T lymphocyte differentiation antigens and fluorescence-activated cell sorter (FACS) analysis were used to detect changes in T lymphocyte subpopulations. Percentages of total T lymphocytes (Thy-1.2-positive), T-helper/inducer lymphocytes (L3T4-positive), and T-cytotoxic/suppressor lymphocytes (Lyt-2-positive) were significantly lower in NO2-exposed animals than in filtered-air-breathing controls. Large T-cytotoxic/suppressor cells were found to be the most susceptible subpopulation. Spleen and body weights of the mice were also determined. There were no differences between body weights of control and exposed animals; however, exposed mice had significantly lower spleen weights. This is the first report providing evidence linking alterations in T lymphocyte subpopulations to acute NO2 exposure at occupational levels. T lymphocytes play a central role in regulatory and effector immunological functions such as mediating delayed hypersensitivity, regulating immunoglobulin production, and lysing virus-infected and neoplastic cells. The biological significance of these findings remains to be established, but it is very likely that functional impairment occurs since an optimal immune response depends upon a proper balance of the T lymphocyte subpopulations. Detection of alterations in T lymphocyte subpopulations using monoclonal antibodies and FACS analysis may provide an extremely sensitive means of demonstrating NO2-induced changes in the immune system.
Subject(s)
Nitrogen Dioxide/toxicity , T-Lymphocytes/classification , Animals , Body Weight/drug effects , Female , Flow Cytometry , Fluorescent Antibody Technique , Mice , Mice, Inbred C57BL , Organ Size/drug effects , Reference Values , Spleen/drug effects , Spleen/immunology , Spleen/pathology , T-Lymphocytes/drug effectsABSTRACT
The effects of ambient level (0.25-0.35 ppm)NO2 on percent spleen cell counts, relative percentages of spleen lymphocyte subpopulations, spleen lymphoid nodule size, and differential peripheral blood cell counts were investigated in 170 young adult male mice following various NO2 exposure periods. The total spleen cell counts, surface IgM-positive lymphocytes and spleen mean lymphoid nodule area were all significantly decreased in the groups exposed to NO2 following extended time periods. The relative percentages of peripheral blood lymphocytes were also significantly decreased in the groups exposed to NO2 for 8 weeks. The mechanism for these observed spleen changes following ambient level NO2 exposure remains unclear, but the results warrant further investigation and concern, especially since such changes may reflect altered immune responsiveness.
Subject(s)
Nitrogen Dioxide/toxicity , Spleen/drug effects , Animals , Blood Cell Count , Cell Count , Male , Mice , Mice, Inbred C57BL , Organ Size/drug effects , Spleen/immunology , Spleen/pathologyABSTRACT
It is recognized that cancer cells may be introduced into circulation during surgical removal of a malignant neoplasm. The fate of these cells depends upon many factors. In this paper we present findings from an animal model which indicate that inhalation of nitrogen dioxide facilitates blood-borne cancer cell metastasis to lungs by injuring lung capillary endothelium and formation of microthrombi. Lung capillaries were evaluated by light and electron microscopy. The main lesions observed were microthrombi and injury to capillary endothelial cells, following 6 weeks of 0.35 +/- 0.05 ppm NO2 exposure. The blood-borne cancer cell metastasis was studied utilizing B16 melanoma cells in C57Bl/6J mice. A correlation was observed between increased incidence of microthrombi, endothelial cell injury and lung metastasis in exposed animals. Other adverse NO2 effects such as impairment of immune system may also participate. Inhalation of nitrogen dioxide and other air pollutants may play a significant role in enhancement of metastasis and blood vessel associated disorders.
Subject(s)
Neoplasm Metastasis , Nitrogen Dioxide/toxicity , Pulmonary Embolism/chemically induced , Administration, Inhalation , Animals , Lung/drug effects , Lung/pathology , Lung/ultrastructure , Male , Mice , Mice, Inbred C57BL , Pulmonary Embolism/pathologyABSTRACT
In this article we report inhalation effects of nitrogen dioxide (NO2) and ozone (O3) mixture as well as O3 alone on blood-borne cancer cell colonization of lungs. The findings are discussed in light of our earlier studies with NO2 exposure alone. In all of these studies the mouse B16 melanoma model was used. Animals were exposed to ambient concentrations of pollutants before melanoma-cell infusion. The results have indicated that inhalation of NO2 played a significant role in facilitation of blood-borne cancer cell spread, while O3 inhalation did not. With respect to mechanisms involved, the role of natural immunity was investigated and its was postulated that nitrogen dioxide may affect cells of the immune system and may in part account for the results. These findings may have direct bearing on dissemination of human cancer cells, since many cancer patients have circulating cancer cells and are exposed daily to noxious air pollutants. Most importantly, this effect may be preventable by reducing air pollution in urban areas.
Subject(s)
Cytotoxicity, Immunologic/drug effects , Lung Neoplasms/pathology , Melanoma/pathology , Neoplastic Cells, Circulating , Nitrogen Dioxide/toxicity , Ozone/toxicity , Air Pollutants/toxicity , Animals , Cell Line , Male , Mice , Spleen/cytology , Spleen/drug effects , Spleen/immunologyABSTRACT
The effects of ambient levels of NO2 on murine splenic T-lymphocyte subpopulations and natural killer cells were investigated. AKR/cum and C57BL/6J mice were exposed, in inhalation chambers, to 0.25 ppm NO2 for 7 wk and 0.35 ppm NO2 for 12 wk, respectively. Monoclonal antibody technology was used in conjunction with fluorescence-activated cell sorter (FACS) analysis to detect quantitative changes in total T-lymphocytes (Thy-1.2-positive), mature T-lymphocytes (Lyt-1-positive), T-helper/inducer lymphocytes (L3T4-positive), T-cytotoxic/suppressor lymphocytes (Lyt-2-positive), and natural killer cells (asialo GM1-positive). Percentages of all T-lymphocyte subpopulations tested and natural killer cells were lower in spleens of mice exposed to NO2 compared to filtered-air controls. This is the first report providing evidence linking alterations in T-lymphocyte subpopulations and natural killer cells to NO2 exposure at ambient levels. Changes in T-lymphocyte subpopulations detected by FACS and correlated to impaired immune function may provide an extremely sensitive means of demonstrating NO2-induced changes in the immune system.