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PubMed2004

Epidemiology and risk factors for hepatitis C in Alaska Natives.

Large cohorts of persons infected with hepatitis C virus (HCV) that include patients with multiple risk exposures and behaviors have been rarely reported. We herein describe a population-based cohort of 759 Alaska Natives (AN) with HCV who were recruited into a long-term follow-up study. History of injection drug use (IDU) was reported by 60.1% and blood transfusion by 14.0%. The most common genotype was 1a (42.0%), followed by 1b (20.3%), 2b (14.7%), 3a (14.3%), and 2a (7.8%). By multivariable analysis, risk exposures (blood transfusion vs. other; P < 0.01; odds ratio [OR], 2.87; 95% confidence interval [CI], 1.51-5.45) and year of infection (P < 0.01; OR, 3.47; 95% CI, 1.34-8.96) were significantly associated with HCV RNA-positivity. Having an RNA concentration >/=2 million copies/mL was associated with male gender (OR, 1.94) and genotype (P < 0.01 overall; 1a vs. 3a: OR, 1.92; 2b vs. 3a: OR, 3.17) by multivariable analysis. In conclusion, the two principal risk exposures for AN infected with HCV (IDU and blood transfusion) are the same as the overall U.S. population. Persons with a history of blood transfusion were more likely to be HCV RNA positive than those without such history. Higher RNA levels found in males may explain the more severe disease previously reported in this group.

Adult↗
PubMed1986

Four primary malignant neoplasms in a single patient.

A 60-year-old Caucasian male, with a previous history of a 10-year occupational exposure to ionizing radiation, chemical carcinogens, and a long history of tobacco and alcohol abuse, developed synchronous squamous cell carcinoma of the floor of the mouth and adenocarcinoma of the lung. Four years later, squamous cell carcinoma of the larynx followed by squamous cell carcinoma of the tongue were diagnosed. In this case report, we suggest that increased exposure to multiple carcinogenic factors may result in an increased incidence of both synchronous and metachronous primary malignant neoplasms.

Adenocarcinoma↗
PubMed2006

El Salvador earthquakes: relationships among acute stress disorder symptoms, depression, traumatic event exposure, and resource loss.

Four and seven weeks after powerful earthquakes in El Salvador, the authors examined the relationships among demographics, traumatic event exposure, social support, resource loss, acute stress disorder (ASD) symptoms, depression, and posttraumatic growth. Participants were 253 college students (Study 1) and 83 people in the community (Study 2). In Study 1, female gender, traumatic event exposure, low social support, and loss of personal characteristic, condition, and energy resources contributed to ASD symptoms and depression. In Study 2, damage to home and loss of personal characteristic and object resources contributed to ASD symptoms and depression. Posttraumatic growth was not associated with ASD symptoms or depression. Findings support the conservation of resources stress theory (Hobfoll, 1998). Resource loss spirals, excessive demands on coping, and exposure to multiple disasters are discussed.

Adult↗
PubMed2002

Lentiviral transduction of P140K MGMT into human CD34(+) hematopoietic progenitors at low multiplicity of infection confers significant resistance to BG/BCNU and allows selection in vitro.

Lentiviral vectors may improve hematopoietic stem cell (HSC) gene transfer because of their enhanced ability to transduce nondividing cells. However, many studies report efficient transduction only at high multiplicities of infection (MOI). This study reports efficient transduction of human CD34(+) cells with a drug resistance gene allowing post-transduction selection using lentivirus under low-MOI conditions that did not require cytokine stimulation or viral concentration. We used the P140K methylguanine-DNA-methyltransferase mutant (P140K MGMT) as the gene insert into a second-generation lentiviral backbone and triple-plasmid transfection to generate vesicular stomatitis virus (VSV)-G protein-pseudotyped virus. The P140K MGMT gene product, O(6)-alkylguanine-DNA-alkyltransferase (AGT), provides protection from the therapeutic drug combination of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the wild-type AGT inhibitor O(6)-benzylguanine (BG). Low-speed spinoculation enhanced transduction more than addition of Polybrene or multiple virus exposures. Addition of cytokines was not required. Low-MOI transduction (< or =1) of human CD34(+) and CD34(+) lin(-) cells with P140K MGMT lentivirus resulted in an average 41% and 89% gene transfer rate as assessed by PCR, respectively, and concordant AGT expression that conferred substantial clonogenic survival advantage after BG/BCNU treatment. During in vitro drug selection, 87% of surviving CD34(+) cell-derived colony-forming units (CFU) were transduced. This work shows the potential utility of lentiviral vectors for drug resistance gene transfer to HSCs for the purpose of in vivo selection and marrow protection. Because drug selection will enrich for transduced progenitors, high MOI can be avoided, improving the safety profile of lentiviral gene transfer.

Antigens, CD34↗
PubMed2002

Antibiotic use and upper respiratory infections: a survey of knowledge, attitudes, and experience in Wisconsin and Minnesota.

BACKGROUND: Public attitudes and expectations contribute to inappropriate antibiotic prescribing and antibiotic resistance. This study assessed knowledge, attitudes, and experiences regarding antibiotic use for respiratory infection or illness. METHODS: Random-digit-dialing telephone surveys of adults and parents of children <5 years old were conducted in Wisconsin and Minnesota during 1999. RESULTS: The survey was completed by 405 adults and 275 parents of children <5 years old. The median age was 32 years for parents and 50 years for adults. Seven percent of parents and 17% of adults believed that antibiotics are never or almost never necessary for bronchitis. More than 70% in each group believed that antibiotics are needed for green or yellow nasal drainage, and nearly half of respondents believed that they knew whether an antibiotic was needed before seeing a physician. Exposure to multiple information sources on antibiotic resistance in the past 6 months was independently associated with a knowledge score greater than or equal to the median for nine questions. CONCLUSIONS: The general public has misconceptions regarding indications for antibiotic use, and this may contribute to inappropriate prescribing. Providing multiple and varied antibiotic-related informational messages may increase knowledge of appropriate antibiotic prescribing and decrease patient demand for antibiotics.

Adult↗
PubMed2002

Evidence of the dose effects of an antitobacco counteradvertising campaign.

OBJECTIVE: The objectives were to assess the cumulative effects of exposure to multiple antitobacco advertisements shown over a 22-month period on smoking uptake, and determine if there is evidence of a dose effect and how this effect operates through response to the campaign's major message theme and antitobacco attitudes. METHODS: A follow-up telephone survey of persons ages 12-20 years was conducted after 22 months of the Florida "truth" antitobacco media campaign. Logistic regression analyses were used to estimate adjusted odds ratios for the likelihood that time-one nonsmokers would remain nonsmokers at time two by levels of confirmed advertisement awareness, self-reported influence of the campaign's message theme, and anti-tobacco industry manipulation attitudes. Separate cohorts are analyzed and controls include gender and time-one susceptibility. RESULTS: The likelihood of nonsmokers remaining nonsmokers increases as the number of ads confirmed, the self-reported influence of the campaign's major message theme, and the level of antitobacco attitudes increases. The pattern to these relationships holds within cohorts of young and older youth and for a cohort that has aged into the early young adult years. Considering all variables simultaneously suggests that ad confirmation operates through its effects on the influence of the message theme and antitobacco industry manipulation attitudes. CONCLUSIONS: There is evidence of a dose effect; however, considering only ad confirmation underestimates this. Antitobacco campaigns that target youth can have effects at least through the early young adult ages. The uniqueness of the Florida campaign may limit the generalization of reported results.

Adolescent↗
PubMed1998

Methyl tertiary butyl ether-induced endocrine alterations in mice are not mediated through the estrogen receptor.

Chronic exposure to methyl tertiary butyl ether (MTBE) altered the rodent tumor incidence of endocrine-sensitive tissues and decreased the incidence of estrogen-dependent uterine cystic hyperplasia in mice. To test the hypothesis that changes in the incidence of tumors in female B6C3F1 mice after MTBE exposure are secondary to endocrine alterations, we exposed female mice to the carcinogenic dose of MTBE vapor (8000 ppm) for 3 or 21 days or 4 or 8 months under conditions similar to a previous 2-year bioassay. MTBE exposure significantly decreased body weight gain and ovary and pituitary weight at 4 and 8 months and uterine weight at all time points. After 8 months of exposure, MTBE significantly increased the length of the estrous cycle by increasing the mean number of days in both the estrus and the nonestrus stages. Histological evaluation of H&E-stained tissues showed a decrease in the number of uterine glands after subchronic MTBE exposure. DNA synthesis, as measured by the incorporation of 5-bromo-2'-deoxyuridine (BrdU), was decreased in uterine glandular and luminal epithelial cells after MTBE exposure for 3 or 21 days or 4 or 8 months. MTBE exposure decreased the number of epithelial layers in the cervix and vagina at all time points. DNA synthesis was decreased in cervical and vaginal epithelium after 21 days of MTBE. Decreased zona reticularis of adrenal glands was found after 4 and 8 months of MTBE exposure without changes in BrdU incorporation. MTBE did not competitively bind to estrogen receptor. MTBE exposure did not alter serum estrogen levels or alter the location or intensity of estrogen receptor immunoreactivity in the uterus, cervix, and vagina. These data indicate that while MTBE exposure causes multiple endocrine-related tissue and cellular responses, these effects are not mediated through the estrogen receptor.

Administration, Inhalation↗
PubMed1987

The evaluation of biological interactions using response surface methodology.

Response surface methodology was employed in the statistical analysis of the combination exposures of genotoxic agents, bischloroethylnitrosourea with cis-diamminedichloroplatinum (II) and cis-diamminedichloroplatinum (II) with X rays. The measured endpoint in each case was sister chromatid exchanges in V79 Chinese hamster cells. The combination experiments employed a factorial design in which cells were treated, in various concentration combinations, with two agents simultaneously. Bis-chloroethylnitrosourea and cis-diamminedichloroplatinum (II) each exhibited curvilinear concentration-related increases in sister chromatid exchanges. X rays exhibited a dose-dependent increase in sister chromatid exchanges. For the cis-diamminedichloroplatinum (II)/X ray combinations, response surface methodology indicates a less-than-additive interaction, suggested by the non-parallel concentration-response curves of one agent at varying concentrations of the other, and a slight dose-dependent increase in sister chromatid exchanges due to X rays alone. Both cis-diamminedichloroplatinum and bis-chloroethylnitrosourea exhibited concentration-related increases in sister chromatid exchanges, cis-diamminedichloroplatinum (II) being 8-10 times (dependent on what level of effect was compared) more potent than bis-chloroethylnitrosourea. For the cis-diamminedichloroplatinum (II)/bis-chloroethylnitrosourea combinations, an increasingly less-than-additive interaction was detected. The analysis of these combinations demonstrates the strength of response surface methodology, a collection of mathematical and statistical techniques for detecting, analyzing and describing the biological effects resulting from exposures to multiple cytotoxic agents. The descriptive ability of these procedures is shown to be useful in that it leads to the suggestion of hypotheses regarding mechanisms of action.

Animals↗
PubMed1984

Enhancement of natural killer cell activity in mice by treatment with a thymic factor.

The administration of a thymic factor, thymostimulin (TP-1), to mice resulted in considerable augmentation of natural killer (NK) cell activity as measured in a short-term assay against 51Cr-labeled YAC-1 target cells. Conditions suitable for detection of the thymostimulin-induced boosting of NK included multiple daily exposures to TP-1 (50 micrograms/kg), and peak levels of reactivity were observed at 2-4 days after discontinuation of treatment. A strict age-dependency of the effect was also observed, with optimal augmentation of NK-cell activity when TP-1 was administered to mice at 4-6 weeks of age. The effect was not limited to TP-1 treatment but was also observed on administration of another thymic factor (thymosin alpha 1). The activated cells responsible for the increased natural cell-mediated cytotoxicity appeared to be typical murine NK cells, judging by both functional and antigenic criteria.

Age Factors↗
PubMed1994

Characterization of cytochrome P4501A induction in medaka (Oryzias latipes) by samples generated from the extraction and processing of coal.

The objective of this study was to characterize cytochrome P4501A induction in medaka liver as a biomarker for detecting polyaromatic hydrocarbon (PAH)-type compounds in samples of processed coal or petroleum. Ethoxyresorufin-O-deethylase (EROD) activity in individual medaka livers was used to asses induction of P4501A following the addition of various samples to aquaria water. Samples included a known P4501A inducer, beta-naphthoflavone, and various processed coal samples, as well as a petroleum-pitch. The sensitivity of detecting significant EROD induction by adding samples to aquaria water was approximately 0.1 mg/L for most samples; however, a coal-tar pitch significantly increased EROD activity at 0.01 mg/L. Different samples induced EROD activity to different extents. All samples elicited a concentration-dependent increase in EROD activity, with maximum EROD induction 2 days after a single administration of xenobiotics to aquaria water. Western blot studies established that induction of EROD activity by all xenobiotics tested was associated with corresponding increased amounts of immunoreactive P4501A. EROD induction was not influenced by gender, by single or multiple xenobiotic exposures, nor by feeding or fasting animals during the course of xenobiotic exposure. The ability of xenobiotics to induce EROD activity in medaka liver did not always correlate with their genotoxic potential determined by bacterial mutagenesis assays. Induction of P4501A in medaka liver appears to provide a convenient, economical, reliable and sensitive indicator for the presence of PAH-type compounds in coal- or petroleum-derived samples.

Animals↗
PubMed1984

Experimental study on the pulmonary absorption and excretion of toluene.

Three exposure levels of toluene were inhaled by dogs for 1 h. Toluene concentrations in expired air, arterial blood and venous blood were repeatedly measured. Absorptions of toluene within one hour of exposure were 25, 56 and 74 mg/kg at 700, 1500 and 2000 ppm respectively (absorption ratio = 27%). The cumulative excretion one hour after exposure was 63% of the absorped material at all three exposure levels. Multiple regression analyses were performed to interconnect the independent variables.

Absorption↗
PubMed1980

[Blood lipid and blood glucose changes during single, multiple and repeated stress].

As soon as various stressors exceed specific thresholds they induce marked metabolic changes in the organism. In a number of studies these facts have been verified experimentally. In our investigations we were able to demonstrate that the pattern of stress-induced changes differs after single and multiple stress exposures and that metoblic alterations in repeated stress situations are modified by habituative and adaptative processes respectively. Stress-induced metabolic mechanisms differently develop for blood lipid fractions and blood glucose. The described mechanisms are explained according to the functions of these blood parameters during stress exposures. The differential analysis of these alterations may be important for the prevention of stress-induced metabolic disorders.

Adult↗
PubMed1996

The effect of 5-lipoxygenase inhibition on Ascaris antigen (Ag)-induced responses in atopic monkeys.

The effects of two 5-lipoxygenase (5LO) inhibitors, ZD2138 or Zileuton, on acute, inflammatory responses to aerosolized Ascaris suum (Ag) were determined in atopic Macaca fascicularis monkeys. Monkeys (n = 6 each group) were dosed with vehicle, 3 or 10 mg/kg ZD2138, or 30 mg/kg Zileuton (p.o.). Both ZD2138 or Zileuton significantly inhibited ex vivo LTB4 production in Ca2+ ionophore-stimulated whole blood from these same monkeys (n = 6 each group) by 45.5% (3 mg/kg ZD2138), 82.5% (10 mg/kg ZD2138) and 84.3% (30 mg/kg Zileuton). ZD2138 (10 mg/kg) reduced bronchoalveolar lavage (BAL) LTE4 levels (65.1% inhibition), BAL neutrophils (88.9% inhibition), and IL-6 (54.0% inhibition) 4h post Ag. Zileuton inhibited these responses and also reduced BAL levels of IL-8 (73.4% inhibition). A second study was performed to evaluate the effects of ZD2138 on chronic Ag-induced responses. Treatment with ZD2138 did not prevent pulmonary inflammation or the development of airway hyperresponsiveness (AHR). Based upon these results, 5LO inhibition significantly reduced ex vivo LTB4 and in vivo LTE4 production as well as several acute inflammatory responses to Ag in the lung. However, ZD2138 did not inhibit more chronic responses following multiple Ag exposure.

Animals↗
PubMed2006

Fulminant hepatic failure and paracetamol overuse with therapeutic intent in febrile children.

OBJECTIVE: To evaluate the risk of fulminant hepatic failure in relation to paracetamol overuse with therapeutic intent in febrile children. METHODS: It was a case control study. Paracetamol ingestion for the current febrile illness was compared between 25 cases of fulminant hepatic failure and 33 hospital age matched controls. RESULTS: Supra-therapeutic doses of paracetamol (mean 145 mg/kg/day) were consumed by all 25 cases compared to none in the control group. Mean paracetamol level in the cases and controls were, respectively, 26.84 mg /dl and 0.051 mg /dl (p< 0.001). The mean duration of paracetamol intake prior to admission in cases was 3. 45 days compared to 1.85 days in the control group. Nineteen, 5 and 3 were, respectively, graded as hepatic encephalopathy grade 1, 2 and 3. All six patients in grade 2 and 3 had hepatomegaly compared to 78% in the grade 1. Four had jaundice and all were in grade 2 or 3. Mean alanine aminotransferase was 2781 U/L None of the randomly selected cases (6) had serological evidence of Hepatitis A, Hepatitis B or Dengue. Three cases died. CONCLUSION: Exposure to multiple supratherapeutic doses of paracetamol is a risk factor to develop fulminant hepatic failure in children with an acute viral like febrile illness.

Acetaminophen↗
PubMed1985

The inorganic dust pneumoconioses.

Collectively, the pneumoconioses represent a spectrum of pulmonary diseases initiated by inorganic dust exposure. Although multiple humoral and cellular immune alterations have been demonstrated in these interstitial and commonly fibrotic lung diseases, the exact role of immune changes in disease pathogenesis presently is undefined. Insight into disease mechanisms may have to await the careful characterization of suitable animal models, along with analysis of local, human bronchopulmonary immune responses through the vehicle of bronchoalveolar lavage.

Asbestosis↗
PubMed2003

The aetiology of posttraumatic stress disorder in four ethnic groups in outpatient psychiatry.

BACKGROUND: PTSD is one of few diagnoses to be defined by its aetiology. At treatment centres specialising in a certain type of trauma, like war, torture or sexual abuse, the aetiology may be regarded as self-explanatory. Recent surveys of general populations reveal high rates of PTSD, often following exposure to multiple traumatic events. Traumas are frequently overlooked in general psychiatric settings and PTSD is underestimated. Such findings indicate the need to conceptualise trauma in terms of multiple events and to examine the aetiology of PTSD amongst patients in everyday psychiatric practice. The present study examines aetiological factors of PTSD in three minority groups at a general psychiatric outpatient clinic. Arabs, Iranians and Turks selected from an entire year's cohort of patients-and a sample of Swedish patients of similar age and gender distribution. METHODS: Histories were collected from 115 patients, both regarding their own traumas and traumas involving relatives and close friends, by means of a questionnaire. A self-rating instrument for PTSD, with no reference to a specific trauma, was used in order to study the relationship between trauma and PTSD outcome. RESULTS: Of the patients, 89% had experienced at least one trauma, and 77% multiple traumatic events. The prevalence of probable PTSD varied between ethnic groups: Iranians 69%, Arabs 59%, Turks 53% and Swedes 29%. In a logistic regression analysis, probable PTSD outcome was associated with multiplicity of relatives' traumas (OR = 3.14), multiplicity of own traumas (OR = 2.56) and belonging to an ethnic minority (OR = 2.44), but not with gender. No patient without a trauma history was positively assessed for probable PTSD. CONCLUSION: The symptomatic syndrome of probable PTSD does not appear in the absence of extreme trauma, lending empirical support to the definition of PTSD. Prevalence increases with multiplicity of traumas, including those involving a relative or close friend. The high prevalence of probable PTSD found in this study warrants screening for trauma among patients, their relatives and close friends, in outpatient psychiatry.

Adult↗
PubMed2004

Effects of physical activity and dietary calcium intake on bone mineral density and osteoporosis risk in a rural Thai population.

The objective of the study was to determine the effects of modifiable risk factors on bone mineral density in postmenopausal Thai women. Dietary calcium intake (g/day), energy expenditure (kcal/day), and sunlight exposure (h/day) were assessed in 129 rural Thai women aged 63 years (range 50 to 84 years). Bone mineral density (BMD) at the femoral neck, lumbar spine, and distal radius were measured by dual-energy X-ray absorptiometry (DXA). The average dietary calcium intake was 236 +/- 188 g/day (mean +/- SD), while the energy expenditure was 2,118 +/- 656 kcal/day with 1.1 +/- 1.7 h of sunlight exposure. In multiple linear regression analysis, dietary calcium intake, energy expenditure, and years since menopause were significant and independent predictors of BMD at various sites. The three factors together accounted for between 35% and 45% of the variance of BMD. The prevalence of osteoporosis (defined as BMD T-scores < or =-2.5) was 33% at the femoral neck, 42% at the lumbar spine, and 35% at the distal radius. The risk of osteoporosis was higher in women with lower dietary calcium intake (< or =138 mg/day; prevalence rate ratio [PRR], 1.4; 95% confidence interval [CI], 1.0 to 1.9), lower energy expenditure (< or =1,682 kcal; PRR, 1.7; 95% CI, 1.2 to 2.3), and greater years since menopause (> or =6 years; PRR, 2.6; 95% CI, 1.2 to 5.8). The population attributable risk fraction of osteoporosis risk due to the three factors was 70%. These results suggest that in the Thai population, low dietary calcium intake and low physical activity together with advancing years since menopause were independent risk factors for low BMD.

Aged↗
PubMed2002

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone.

Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.

Animals↗