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Biomedical subjects

L Ryan

Publications and source records attributed to L Ryan.

At least 55 records · Page 3Linked to original sources
PubMed2000

Risk of internal cancers from arsenic in drinking water.

The U.S. Environmental Protection Agency is under a congressional mandate to revise its current standard for arsenic in drinking water. We present a risk assessment for cancers of the bladder, liver, and lung from exposure to arsenic in water, based on data from 42 villages in an arseniasis-endemic region of Taiwan. We calculate excess lifetime risk estimates for several variations of the generalized linear model and for the multistage-Weibull model. Risk estimates are sensitive to the model choice, to whether or not a comparison population is used to define the unexposed disease mortality rates, and to whether the comparison population is all of Taiwan or just the southwestern region. Some factors that may affect risk could not be evaluated quantitatively: the ecologic nature of the data, the nutritional status of the study population, and the dietary intake of arsenic. Despite all of these sources of uncertainty, however, our analysis suggests that the current standard of 50 microg/L is associated with a substantial increased risk of cancer and is not sufficiently protective of public health.

Adult↗
PubMed2000

Particle concentrations in urban microenvironments.

Although ambient particulate matter has been associated with a range of health outcomes, the health risks for individuals depend in part on their daily activities. Information about particle mass concentrations and size distributions in indoor and outdoor microenvironments can help identify high-risk individuals and the significant contributors to personal exposure. To address these issues in an urban setting, we measured particle count concentrations in four size ranges and particulate matter (3/4) 10 microm (PM(10)) concentrations outdoors and in seven indoor microenvironments in Boston, Massachusetts. Particle counts and PM(10) concentrations were continuously measured with two light-scattering devices. Because of the autocorrelation between sequential measurements, we used linear mixed effects models with an AR-1 autoregressive correlation structure to evaluate whether differences between microenvironments were statistically significant. In general, larger particles were elevated in the vicinity of significant human activity, and smaller particles were elevated in the vicinity of combustion sources, with indoor PM(10) concentrations significantly higher than the outdoors on buses and trolleys. Statistical models demonstrated significant variability among some indoor microenvironments, with greater variability for smaller particles. These findings imply that personal exposures can depend on activity patterns and that microenvironmental concentration information can improve the accuracy of personal exposure estimation.

Air Pollutants↗
PubMed2000

Progression of microalbuminuria to proteinuria in type 1 diabetes: nonlinear relationship with hyperglycemia.

While small clinical trials have shown that improved glycemic control reduces the risk of progression of microalbuminuria to proteinuria, two recent clinical trials did not confirm this finding. We sought to reconcile the contradictory evidence by examining the dose-response relationship between hyperglycemia and progression of microalbuminuria to proteinuria in individuals with type 1 diabetes and microalbuminuria (n = 312) who were followed for 4 years with repeated assessments of urinary albumin excretion. Since 33 patients did not participate in follow-up (10.6%), data for 279 patients were analyzed. Urinary albumin excretion level worsened to proteinuria in 40 (4.1 per 100 person-years). To examine the dose-response relationship, baseline HbA1c was divided into four roughly equal groups using the cut points 8, 9, and 10%. The incidence rate varied significantly among the four groups (P = 0.008). Among those with HbA1c <8.0%, the incidence rate of progression was only 1.3 per 100 person-years, while it was 5.1, 4.2, and 6.7 per 100 person-years in the three other groups. We used generalized additive models to examine the dose-response curve using HbA1c as a continuous variable and found that the risk of progression rises steeply between an HbA1c of 7.5-8.5% and then remains approximately constant across higher levels. In conclusion, the results of this study suggest that, in patients with microalbuminuria, the risk of progression to overt proteinuria can be reduced by improved glycemic control only if the HbA1c is maintained below 8.5%. Moreover, below that value, the risk declines as the level of HbA1c decreases.

Adolescent↗
PubMed1999

Cardiovascular malformations: changes in prevalence and birth status, 1972-1990.

Through an ongoing hospital-based active malformation surveillance program, we identified cardiovascular malformations (CVMs) in 3.3 per 1,000 liveborn and stillborn infants, and fetuses from pregnancies terminated electively during a 15-year period. We excluded the children of mothers who had planned delivery elsewhere, but were transferred for care of anomalies that had been detected in prenatal screening. Birth status changed markedly during the study with a significant increase in elective terminations of fetuses with a CVM from 0 to 22% (P < 0.01 based on a test for trend). The proportion of liveborn infants with CVMs decreased from 90% to 73% (P < 0.01); the frequency of stillbirths did not change. During the study period, there was a significant increase in the prevalence of CVMs in all births (P < 0.01) and elective terminations (P < 0.01). The increase in liveborn prevalence was not statistically significant (P = 0.08). Stillborn prevalence was unchanged. The number of mothers having prenatal ultrasonography (P < 0.01 for trend) and amniocentesis (P < 0.01 for trend) increased steadily. There were significant increases in the proportion of mothers having any ultrasound examination (P < 0.01 for trend), the number of initial ultrasound examinations occurring in the second trimester (P < 0.01 for trend), and the proportion of mothers having amniocentesis (P < 0.01 for trend). There was a significant increasing trend in the proportion of mothers who were 35 years and older (10% in 1972-1974, 26% in 1988-1990, P < 0.01). This hospital-based active surveillance program suggests that more frequent elective terminations had a significant effect on overall birth prevalence of CVMs. This trend would not have been detected by most other surveillance systems which determine prevalence of common birth defects from birth certificates and other forms of administrative reporting, and exclude elective terminations of pregnancy.

Abortion, Induced↗
PubMed1999

Transplantation of alginate microcapsules: generation of antibodies against alginates and encapsulated porcine islet-like cell clusters.

BACKGROUND: Microencapsulation of islets of Langherhans in alginate poly-L-lysine capsules provides an effective protection against cell-mediated immune destruction, and ideally should allow the transplantation of islets in the absence of immunosuppression. It has previously been suggested that alginate rich in mannuronic acid (high M) is more immunogenic than alginate rich in guluronic acid (high G). The ability of these alginates to induce an antibody response in the recipient or act as an adjuvant to antibody responses against antigens leaked from the capsule was investigated in the present study. METHODS: Empty capsules made from these different types of alginate were transplanted intraperitoneally to Wistar rats or Balb/c mice. In addition, some animals were also injected with bovine serum albumin to assess the ability of the alginates to act as an adjuvant to this antigen. Antibody responses to intraperitoneally transplanted free and microencapsulated fetal porcine islet like cell clusters (ICC) were also evaluated, in animals treated with or without cyclosporine. RESULTS: Antibodies against high M-alginate capsules were detected in the sera of mice transplanted with this capsule type. However, this response was not seen after the transplantation of high G capsules. When Wistar rats were used as recipients, no antibody responses were detected against any type of alginate capsules. Neither type of capsule acted as an adjuvant. Antibodies against ICC were present, in rats transplanted with both nonencapsulated and encapsulated ICCs. Administration of cyclosporine could abolish this production of antibodies against ICC. CONCLUSIONS: High G-alginate capsules are less immunogenic than high M capsules. Because encapsulation did not protect against the generation of antibodies against ICC, it can be assumed that antigen leakage from the capsules occurs, as no evidence was found for capsules breaking in vivo.

Adjuvants, Immunologic↗
PubMed1999

Prevention of high-risk behaviors in adolescent women.

PURPOSE: To better delineate the impact of health risk behaviors on adolescent women's current and future health and development. METHOD: The Commonwealth Fund Survey of Adolescent Health, a national survey of adolescents in Grades 5-12 designed to better understand their health and health care needs, was used as the basis for this study. Survey data were collected in 1997 from a total of 6730 adolescents (3568 females, 3162 males). Areas examined include smoking, drinking, use of other drugs, violence, safety, reproductive risks, and the prevention of risk behaviors in adolescent women. RESULTS: Adolescent women are almost equally likely to smoke, drink, and engage in other substance use as their male counterparts, but with increased health risks. Different motivations for engaging in risk behavior also are evident. Adolescent women are also more likely than adolescent men to experience physical abuse, and they are twice as likely to be sexually abused. CONCLUSIONS: Effective prevention programs need to recognize that the motivations for engaging in risk behaviors may differ by gender. Developmental awareness, proper assessment, and pivotal institutions can provide and shape what is needed for healthy development.

Adolescent↗
PubMed1999

Dose-rate effects of ethylene oxide exposure on developmental toxicity.

In risk assessment, evaluating a health effect at a duration of exposure that is untested involves assuming that equivalent multiples of concentration (C) and duration (T) of exposure have the same effect. The limitations of this approach (attributed to F. Haber, Zur Geschichte des Gaskrieges [On the history of gas warfare], in Funf Vortrage aus den Jahren 1920-1923 [Five lectures from the years 1920-1923], 1924, Springer, Berlin, pp. 76-92), have been noted in several studies. The study presented in this paper was designed to specifically look at dose-rate (C x T) effects, and it forms an ideal case study to implement statistical models and to examine the statistical issues in risk assessment. Pregnant female C57BL/6J mice were exposed, on gestational day 7, to ethylene oxide (EtO) via inhalation for 1.5, 3, or 6 h at exposures that result in C x T multiples of 2100 or 2700 ppm-h. EtO was selected because of its short half-life, documented developmental toxicity, and relevance to exposures that occur in occupational settings. Concurrent experiments were run with animals exposed to air for similar periods. Statistical analysis using models developed to assess dose-rate effects revealed significant effects with respect to fetal death and resorptions, malformations, crown-to-rump length, and fetal weight. Animals exposed to short, high exposures of EtO on day 7 of gestation were found to have more adverse effects than animals exposed to the same C x T multiple but at longer, lower exposures. The implication for risk assessment is that applying Haber's Law could potentially lead to an underestimation of risk at a shorter duration of exposure and an overestimation of risk at a longer duration of exposure. Further research, toxicological and statistical, are required to understand the mechanism of the dose-rate effects, and how to incorporate the mechanistic information into the risk assessment decision process.

Administration, Inhalation↗
PubMed1999

Disease-modifying antirheumatic drugs.

Rheumatologists now seem to accept that early treatment of patients with rheumatoid arthritis with disease-modifying antirheumatic drugs is required if erosions are to be prevented. Methotrexate remains the most popular disease-modifying antirheumatic drug and is used in the most popular combination treatments, although the dose needs to be reduced in the elderly and those with renal dysfunction. The combination of sulfasalazine, methotrexate with reducing high-dose prednisolone, is demonstrated to be cost-effective in patients with rheumatoid arthritis, but although several other combinations have been reported effective in patients with rheumatoid arthritis, most trials do not have the power to provide a definitive answer as to the best combination available, if one exists.

Antirheumatic Agents↗
PubMed1999

Statistical methods for developmental toxicity. Analysis of clustered multivariate binary data.

This paper discusses some of the statistical issues that arise from developmental toxicity studies, wherein pregnant mice are exposed to chemicals in order to assess possible adverse effects on developing fetuses. We begin with a review of some current approaches to risk assessment, based on NOAELs, and provide justification for the use of methods based on dose-response models. Due to the hierarchical nature of the data, such models are more complicated in the present context than, say, in cancer studies. For example, multivariate binary outcomes arise when each fetus in a litter is assessed for the presence of malformations and/or low birth weight. We describe a multivariate exponential family model that works well for these data and that is flexible in terms of allowing response rates to depend on cluster side. Maximum likelihood estimation of model parameters and the construction of score tests for dose effect are briefly discussed. Results are illustrated with data from several NTP studies.

Animals↗
PubMed1999

Consequence of Nramp1 deletion to Mycobacterium tuberculosis infection in mice.

129sv mice functionally deleted of the antimicrobial resistance gene, Nramp1, were found to be as resistant as wild-type mice to infection with the virulent H37Rv strain of Mycobacterium tuberculosis, as determined by monitoring bacterial growth in major organs and recording host survival times. Death of infected mice of both types was associated with extensive infection-induced pathology in the lungs but not in other major organs. These findings are in keeping with the view that Nramp1 is of limited importance in resistance to tuberculosis in mice.

Animals↗
PubMed1999

Vaccinated mice remain more susceptible to Mycobacterium tuberculosis infection initiated via the respiratory route than via the intravenous route.

Mice given Mycobacterium tuberculosis bacilli via the respiratory route succumbed much sooner to infection than mice given 1,000 times more bacilli via the intravenous route. Vaccination provided increased protection to an M. tuberculosis challenge infection; however, mice infected via the respiratory route remained much more susceptible.

Administration, Inhalation↗
PubMed1998

Procedures for calculating benchmark doses for health risk assessment.

Safety assessment for noncancer health effects generally has been based upon dividing a no observed adverse effect (NOAEL) by uncertainty (safety) factors to provide an acceptable daily intake (ADI) or reference dose (RfD). Since the NOAEL does not utilize all of the available dose-response data, allows higher ADI from poorer experiments, and may have an unknown, unacceptable level of risk, the benchmark dose (BD) with a specified, controlled low level of risk has become popular as an adjunct to the NOAEL or the low observed adverse effect level (LOAEL) in the safety assessment process. The purpose of this paper is to summarize statistical procedures available for calculating BDs and their confidence limits for noncancer endpoints. Procedures are presented and illustrated for quantal (binary), quasicontinuous (proportion), and continuous data. Quasicontinuous data arise in developmental studies where the measure of an effect for a fetus is quantal (normal or abnormal) but the experimental unit is the mother (litter) so that results can be expressed as the proportion of abnormal fetuses per litter. However, the correlation of effects among fetuses within a litter poses some additional statistical problems. Also, developmental studies usually include some continuous measures, such as fetal body weight or length. With continuous data there generally is not a clear demarcation between normal and adverse measurements. In such cases, extremely high and/or low measurements at some designated percentile(s) can be considered abnormal. Then the probability (risk) of abnormal individuals can be estimated as a function of dose. The procedure for estimating a BD with continuous data is illustrated using neurotoxicity data. When multiple measures of adverse effects are available, a BD can be estimated based on a selected endpoint or the appearance of any combination of endpoints. Multivariate procedures are illustrated using developmental and reproductive toxicity data.

Animals↗
PubMed1998

Human osteoarthritic cartilage matrix vesicles generate both calcium pyrophosphate dihydrate and apatite in vitro.

Calcium crystals in osteoarthritic (OA) joints promote enzymatic degradation of articular tissues. Matrix vesicles provide a nidus for calcium crystal formation in chick epiphyseal and mature porcine articular cartilage. In order to examine a potential role for matrix vesicles from OA cartilage in generating pathologic crystals, we sought to determine whether vesicles derived from human OA cartilage (OAMV) could mineralize; and we characterized the resultant mineral species. OAMV were isolated and examined for alkaline phosphatase (AP) and nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity. OAMV ATP-dependent and independent mineralization were measured in a radiometric biomineralization assay, and newly formed OAMV crystals were examined using Fourier transform infrared spectroscopy (FTIR) and compensated polarized light microscopy. The mean specific activity of OAMV AP was approximately 6 times higher and NTPPPH activity 11 times lower than that of previously characterized, mature, porcine, articular cartilage vesicles. OAMV progressively precipitated 45Ca over time both in the presence and absence of ATP. The FTIR spectra of mineral formed in ATP-dependent assays most closely resembled the standard spectrum for calcium pyrophosphate dihydrate (CPPD). The FTIR spectra of OAMV mineral formed in the absence of ATP closely resembled apatite. These data support the hypothesis that OAMV may form mineral phases of two key crystals found in degenerating cartilage and provide further evidence for the role of matrix vesicles in pathologic articular cartilage biomineralization.

Aged↗
PubMed1998

The prenatal detection of significant alcohol exposure with maternal blood markers.

OBJECTIVE: To examine the efficacy of a combination of 4 blood markers of alcohol use in detecting alcohol-abusing pregnant women. STUDY DESIGN: Two new markers of alcohol use, whole blood-associated acetaldehyde and carbohydrate-deficient transferrin, and 2 traditional markers of alcohol use, gamma-glutamyl transpeptidase and mean red blood cell volume, were measured in the blood of pregnant women. Each woman was interviewed about alcohol and drug use, medical and obstetric histories, and nutrition. Each infant was examined by a clinician who was blinded to exposure status. RESULTS: All of the women who reported drinking an average of 1 or more ounces of absolute alcohol per day had at least 1 positive blood marker. The infants of mothers with 2 or more positive markers had significantly smaller birth weights, lengths, and head circumferences than the infants with negative maternal screens. The presence of 2 or more positive markers was more predictive of infant outcome than any self-reporting measure. CONCLUSIONS: These markers, which detect more at-risk pregnant women than self-reporting methods, could lead to better efforts at detection and prevention of alcohol-induced fetal damage.

Acetaldehyde↗
PubMed1998

Association of petrochemical exposure with spontaneous abortion.

OBJECTIVES: To assess the association between petrochemical exposure and spontaneous abortion, a retrospective epidemiological study in a large petrochemical complex in Beijing, China was conducted. METHODS: Plant employment records identified 3105 women who were married, were 20-44 years of age, and had never smoked. Of those, 3070 women (98.8%) reported at least one pregnancy. From this group, 2853 (93%) of the women participated in the study. According to their plant employment record, about 57% of these women workers reported occupational exposure to petrochemicals during the first trimester of their pregnancy. Trained interviewers administered a standardised questionnaire to this group of women and their husbands, collecting information on reproductive history, pregnancy outcomes, employment history, occupational exposure, smoking habits, alcohol consumption, indoor air pollution, and demographic variables. The results from the womens' first pregnancies were analysed. RESULTS: There was a significantly increased risk of spontaneous abortion for women working in all of the production plants with frequent exposure to petrochemicals (8.8%; range of 5.8%-9.8%) compared with those working in nonchemical plants (2.2%; range of 0.0%-7.1%). Also, when a comparison was made between exposed and non-exposed groups within each plant, exposure to petrochemicals was consistently associated with an increased risk of spontaneous abortion. The overall odds ratio (OR) was 2.7 (95% confidence interval (95% CI) 1.8 to 3.9) after adjusting for potential confounders. When the analysis was performed with the exposure information obtained from the women' interview responses for (self reported) exposures, the estimated OR for spontaneous abortions was 2.9 (95% CI 2.0 to 4.0). The analysis was repeated by excluding those 452 women who provided inconsistent reports between recalled exposure and work history, and a comparable risk of spontaneous abortion (OR 2.9; 95% CI 2.0 to 4.4) was found. In analyses for exposure to specific chemicals, an increased risk of spontaneous abortion was found with exposure to most chemicals, and the results for benzene (OR 2.5; 95% CI 1.7 to 3.7), gasoline (OR 1.8; 95% CI 1.1 to 2.9), and hydrogen sulphide (OR 2.3; 95% CI 1.2 to 4.4) were significant. CONCLUSION: An increased risk of spontaneous abortion was found associated with the exposure to petrochemicals, including benzene, gasoline, and hydrogen sulphide.

Abortion, Spontaneous↗