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Biomedical subjects

L M Ryan

Publications and source records attributed to L M Ryan.

At least 19 recordsLinked to original sources
PubMed2006

Modeling particle exposure in U.S. trucking terminals.

Multi-tiered sampling approaches are common in environmental and occupational exposure assessment, where exposures for a given individual are often modeled based on simultaneous measurements taken at multiple indoor and outdoor sites. The monitoring data from such studies is hierarchical by design, imposing a complex covariance structure that must be accounted for in order to obtain unbiased estimates of exposure. Statistical methods such as structural equation modeling (SEM) represent a useful alternative to simple linear regression in these cases, providing simultaneous and unbiased predictions of each level of exposure based on a set of covariates specific to the exposure setting. We test the SEM approach using data from a large exposure assessment of diesel and combustion particles in the U.S.trucking industry. The exposure assessment includes data from 36 different trucking terminals across the United States sampled between 2001 and 2005, measuring PM2.5 and its elemental carbon (EC), organic carbon (OC) components, by personal monitoring, and sampling at two indoor work locations and an outdoor "background" location. Using the SEM method, we predict the following: (1) personal exposures as a function of work-related exposure and smoking status; (2) work-related exposure as a function of terminal characteristics, indoor ventilation, job location, and background exposure conditions; and (3) background exposure conditions as a function of weather, nearby source pollution, and other regional differences across terminal sites. The primary advantage of SEMs in this setting is the ability to simultaneously predict exposures at each of the sampling locations, while accounting for the complex covariance structure among the measurements and descriptive variables. The statistically significant results and high R2 values observed from the trucking industry application supports the broader use of this approach in exposure assessment modeling.

Carbon↗
PubMed2005

Cementum and dentin in hypophosphatasia.

Hypophosphatasia (HPP) often leads to premature loss of deciduous teeth, due to disturbed cementum formation. We addressed the question to what extent cementum and dentin are similarly affected. To this end, we compared teeth from children with HPP with those from matched controls and analyzed them microscopically and chemically. It was observed that both acellular and cellular cementum formation was affected. For dentin, however, no differences in mineral content were recorded. To explain the dissimilar effects on cementum and dentin in HPP, we assessed pyrophosphate (an inhibitor of mineralization) and the expression/activity of enzymes related to pyrophosphate metabolism in both the periodontal ligament and the pulp of normal teeth. Expression of nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) in pulp proved to be significantly lower than in the periodontal ligament. Also, the activity of NPP1 was less in pulp, as was the concentration of pyrophosphate. Our findings suggest that mineralization of dentin is less likely to be under the influence of the inhibitory action of pyrophosphate than mineralization of cementum.

Adolescent↗
PubMed2003

Predictors of whole-body vibration levels among urban taxi drivers.

To identify a set of important WBV predictors that could be used to develop a statistical instrument for exposure assessment in a large epidemiologic study, a total of 432 WBV measures were taken from a sample of 247 male drivers in Taipei City, Taiwan. In accordance with the ISO 2631-1 (1997) methods, we measured the frequency-weighted vertical acceleration (z-axis) over drivers' seat surface, under conditions representing different types of rides (vacant vs. short vs. long) assigned to random destinations. Mixed effect models were used to analyse the WBV data including repeated measures. For this group of urban taxi drivers regularly exposed to WBV of low intensity (mean = 0.31 ms( - 2), ranging from 0.17 to 0.55 ms( - 2) r.m.s.), our analyses indicated that average driving speed was the primary predictor (p < 0.0001). As average driving speed increased, measured vertical acceleration increased in a quadratic-linear manner (p < 0.0001). Other WBV predictors, after adjusting for the effects of other covariates, included automobile manufacturer (p = 0.02), engine size (p = 0.04), body weight (p = 0.002), age (p = 0.02), use of seat cushion (p = 0.03), and traffic period (p = 0.02). Our study suggests that a similar statistical approach could be employed in future studies to improve the quality and efficiency of WBV exposure assessment in professional drivers.

Acceleration↗
PubMed2002

Comparative calcification of native articular cartilage matrix vesicles and nitroprusside-generated vesicles.

OBJECTIVE: Articular cartilage matrix vesicles generate calcium pyrophosphate- and basic calcium phosphate-like mineral in vitro. We sought to determine the morphologic features and calcifying capacity of sodium nitroprusside (SNP)-induced vesicles for comparison to those of controls. METHODS: Porcine articular cartilage was exposed to 1 mM SNP for 24 h and vesicles were isolated by enzymatic digestion and serial ultracentrifugation. Control vesicles were derived from an equal weight of untreated articular cartilage. Vesicles-containing fractions pelleted at 2 x 10(5) g x min (pellet I), 3 x 10(6) g x min (pellet II, the heavy vesicle fraction) and 8 x 10(6) g x min (pellet III, the light vesicle fraction) were analysed for Lowry protein content, nucleoside triphosphate pyrophosphohydrolase specific activity (NTPPPH) and ATP-dependent calcifying capacity. RESULTS: Electron micrographs (EM) revealed two populations of vesicular structures in both SNP and control pellets. In most experiments, there were no significant differences between the protein contents or ATP-dependent calcium accumulation of SNP vesicles compared to control vesicles. SNP vesicles in pellets I and II had lower NTPPPH activities than their respective controls, P < or = 0.01. CONCLUSIONS: Our data confirmed that 24-hour treatment with the apoptosis-inducing agent did not increase matrix vesicle protein or alter the calcifying activity of vesicles compared to those from control cartilage. SNP did generate vesicles with lower NTPPPH specific activity in most experiments. SNP vesicles, although morphologically similar to controls, are not biochemically identical to them.

Animals↗
PubMed2002

Reliability of serial urine HCG as a biomarker to detect early pregnancy loss.

BACKGROUND: To examine the reliability of HCG as a biomarker for early pregnancy loss, five experienced researchers independently assessed data from 153 menstrual cycles, determining whether each cycle represented 'no conception,' a 'continuing conception' or a 'conception lost.' METHODS: Urine samples were analysed by immunoradiometric assay using a combination of capture antibodies for the intact heterodimer (B109) and for an epitope common to the beta subunit and the beta core fragment (B204). For each cycle, HCG data were presented as graphs of daily assay results. Summary statistics for HCG assays from 46 women who had undergone bilateral tubal ligation represented baseline values. RESULTS: Pairwise agreement among the assessors for any of the three options ranged from 78-89%. At least three experts agreed for 147 cycles (96%), accounting for 28 conception losses and 19 continuing conceptions. The multi-rater kappa was 0.62 for the conception lost category and 0.68 for continuing conceptions, indicating substantial agreement. CONCLUSION: The main sources of disagreement involved deciding whether there was sufficient information for assessment, interpreting cycle parameters such as cycle length or bleeding event, and interpreting a distinct HCG rise pattern that does not exceed the baseline value obtained from the sterilized women.

Abortion, Spontaneous↗
PubMed2001

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

Administration, Oral↗
PubMed2001

The teratogenicity of anticonvulsant drugs.

BACKGROUND: The frequency of major malformations, growth retardation, and hypoplasia of the midface and fingers, known as the anticonvulsant embryopathy, is increased in infants exposed to anticonvulsant drugs in utero. However, whether the abnormalities are caused by the maternal epilepsy itself or by exposure to anticonvulsant drugs is not known. METHODS: We screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. RESULTS: The combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants. CONCLUSIONS: A distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself.

Abnormalities, Drug-Induced↗
PubMed2001

Transforming growth factor beta-1 stimulates articular chondrocyte elaboration of matrix vesicles capable of greater calcium pyrophosphate precipitation.

Objective To determine the role of transforming growth factor beta1 (TGFbeta) in early calcium pyrophosphate formation by measuring its effects on articular chondrocyte matrix vesicle (MV) formation, specific activity of the inorganic pyrophosphate(PPi)-generating enzyme nucleoside triphosphate pyrophospho-hydrolase (NTPPPH) and biomineralization capacity. Methods MV elaborated from mature porcine chondrocyte monolayers+/-TGFbeta were compared for protein content, NTPPPH activity, and ATP-dependent biomineralization. Precipitation of calcium pyrophosphate mineral phases by MV was determined by a radiometric assay and by Fourier transform infrared spectroscopy (FTIR). Results MV from monolayers exposed to TGFbeta were enriched in NTPPPH activity compared to MV from control monolayers (P< 0.01) and precipitated more calcium/mg MV protein than controls (P</= 0.01). FTIR spectra of mineral generated by monolayer-elaborated MV were consistent with poorly crystalline CPPD. Conclusions TGFbeta is capable of increasing the capacity of articular chondrocyte-derived MV to generate PPi via NTPPPH and precipitate calcium in the form of CPPD mineral. These data support the concept that this growth factor plays a key role in cartilage matrix CPPD deposition.

Animals↗
PubMed2001

Effects of exposure to organic solvents on menstrual cycle length.

To investigate the association between organic solvent exposure and menstrual disturbance, we conducted a cross-sectional study among 1408 petrochemical workers in China. Based on an industrial hygiene evaluation, we classified the workshops according to the presence or absence of organic solvents (benzene, styrene, toluene, or xylene). We used logistic regression to estimate odds ratios and 95% confidence intervals for prolonged menstrual cycle length (oligomenorrhea: average cycle length > 35 days during the previous year) associated with the exposure. After adjustment for confounders, each additional year of work in an exposed workshop was associated with a 7% increase in oligomenorrhea (odds ratio, 1.07; 95% confidence interval, 1.00 to 1.14). Compared with no exposure, 3 or more years of exposure was associated with a 53% increase in oligomenorrhea (odds ratio, 1.53; 95% confidence interval, 1.00 to 2.34). We concluded that exposure to organic solvents is associated with a trend toward increased frequency of oligomenorrhea.

Adult↗
PubMed2001

Synthesis of evidence from epidemiological studies with interval-censored exposure due to grouping.

We describe a method for assessing dose-response effects from a series of case-control and cohort studies in which the exposure information is interval censored. The interval censoring of the exposure variable is dealt with through the use of retrospective models in which the exposure is treated as a multinomial response and disease status as a binary covariate. Polychotomous logistic regression models are adopted in which the dose-response relationship between exposure and disease may be modeled in a discrete or continuous fashion. Partial conditioning is possible to eliminate some of the nuisance parameters. The methods are applied to the motivating study of the relationship between chorionic villus sampling and the occurrence of terminal transverse limb reduction.

Biometry↗
PubMed2001

Variations in site and levels of expression of chondrocyte nucleotide pyrophosphohydrolase with aging.

The aim of this study was to identify changes in cartilage intermediate layer protein/nucleotide pyrophosphohydrolase (CILP/NTPPH) expression in articular cartilage during aging. Adult (3-4 years old) and young (7-10 days old) porcine articular hyaline cartilage and fibrocartilage were studied by Northern blot analysis, in situ hybridization, and immunohistochemistry using a complementary DNA (cDNA) probe encoding porcine CILP/NTPPH and antibody to a synthetic peptide corresponding to a CILP/NTPPH sequence. Northern blot analysis of chondrocytes showed lower expression of CILP/NTPPH messenger RNA (mRNA) in young cartilage than in adult cartilage. In adult cartilage, extracellular matrix from the surface to the middeep zone was immunoreactive for CILP/NTPPH, especially in the pericellular matrix surrounding the middeep zone chondrocytes. In young cartilage, chondrocytes were moderately immunoreactive for CILP/NTPPH throughout all zones except the calcified zone. The matrix of young cartilage was negative except in the superficial zone. In young cartilage, CILP/NTPPH mRNA expression was undetectable. In adult cartilage, chondrocytes showed strong mRNA expression for CILP/NTPPH throughout middeep zones. Protein and mRNA signals were not detectable below the tidemark. CILP/NTPPH secretion into matrix around chondrocytes increases with aging. In this extracellular site it may generate inorganic pyrophosphate and contribute to age-related calcium pyrophosphate dihydrate crystal deposition disease.

Aging↗
PubMed2000

The ank gene story.

The underlying molecular defect resulting in the abnormal calcification observed in ank/ank mice has been identified. The responsible nonsense mutation affects the protein product of ank, resulting in diminished production of extracellular inorganic pyrophosphate, an important inhibitor of nucleation and of the growth of apatite crystals. The ank gene product is one of several cell membrane proteins, including ectonucleoside triphosphate pyrophosphohydrolase enzymes and alkaline phosphatase, that regulate extracellular inorganic pyrophosphate levels and thereby regulate mineralization.

Animals↗
PubMed2000

Digit effects produced by prenatal exposure to antiepileptic drugs.

The hypothesis tested was that digit anomalies among individuals exposed in utero to antiepileptic drugs (AED) are best identified by a systematic search, including radiographs and dermatoglyphics, rather than relying only on visual inspection. A systematic search was made for five types of digit abnormalities in 46 AED-exposed individuals ages 5-29 years in comparison with controls: visible anomalies, size of fingernails, dermal ridge patterns, length of metacarpals and phalanges, and qualitative changes in the distal phalanges. Among the AED-exposed, nail size was not decreased. However, there was a 10.8% frequency of digit anomalies, a 12% frequency of three or more arch patterns, and significant shortening and qualitative changes in the distal phalanges, all of which are consistent with the fetal effects of AED. Among the 42 individuals who underwent all evaluations, 14.3% had two or more of these abnormalities, most of which would not be identified by clinical inspection. This frequency is much higher in these AED-exposed individuals than in the general population. Radiographs in 13 individuals over a period of several years showed that the changes in the phalanges and metacarpals persisted.

Abnormalities, Drug-Induced↗
PubMed2000

Anticonvulsant teratogenesis 4: inter-rater agreement in assessing minor physical features related to anticonvulsant therapy.

BACKGROUND: We report on inter-rater agreement in the assessment of newborn infants with respect to a range of minor physical features in a cohort study of the fetal effects of maternal anticonvulsant use during pregnancy. METHODS: Infants from three groups (exposed to anticonvulsants, seizure history but no medication exposure, and unexposed controls) were examined by both a pediatrician/teratologist, who was blinded with respect to the mother's exposure status, and an unblinded research assistant. Agreement on assessments for selected anomalies associated with anticonvulsant therapy was measured by kappa-statistics, as well as by more sensitive log-linear modeling techniques, which allow examination of possible covariate effects on the strength of agreement. Although the physician and research assistant agreed on a high proportion of cases (80-90%), kappa values were modest (0.2-0. 5), partly because of the low prevalence of the anomalies considered. To explore how agreement varies within subgroups, we used recently developed methods for studying agreement based on log-linear models. RESULTS: Log-linear modeling indicated that there was substantial variation in pattern of agreement between different individual research assistants but that other factors (e.g., exposure category, sex, and birthweight) did not appear to be related to agreement. Our results suggest that research assistants with more experience showed the highest degree of agreement with the physicians. CONCLUSIONS: Our results have implications for both clinical practice and epidemiologic research and underline the importance of thorough training of staff in the definitions to be used and also the need for multiple independent assessments of these subtle anomalies.

Abnormalities, Drug-Induced↗
PubMed2000

Expression of cartilage intermediate layer protein/nucleotide pyrophosphohydrolase parallels the production of extracellular inorganic pyrophosphate in response to growth factors and with aging.

OBJECTIVE: To evaluate the role of the extracellular inorganic pyrophosphate (ePPi)-generating ectoenzyme cartilage intermediate layer protein/nucleotide pyrophosphohydrolase (CILP/NTPPH) in chondrocyte PPi elaboration, we studied CILP/NTPPH expression in response to growth factors during aging. METHODS: Porcine chondrocytes from adult (3-4-year-old) and young (2-week-old) animals were stimulated with transforming growth factor beta1 (TGFbeta1), which enhances ePPi elaboration, and/or insulin-like growth factor 1 (IGF-1), which diminishes ePPi elaboration. Measurements of ePPi, NTPPH enzyme activity, Western blot analysis, reverse transcriptase-polymerase chain reaction (RT-PCR), and Northern blot analysis were performed. RESULTS: Elaboration of ePPi into conditioned media from adult chondrocytes was significantly increased by TGFbeta1 and significantly inhibited by IGF-1, but no significant differences were observed in young chondrocytes. The protein levels of CILP/NTPPH by Western analysis in the media from adult and young porcine chondrocytes were increased by TGFbeta1. RT-PCR and Northern analysis showed that CILP/NTPPH messenger RNA (mRNA) expression in both adult and young chondrocytes was increased by TGFbeta1 and decreased by IGF-1, but these changes were less significant in the young chondrocytes. Basal and TGFbeta1-up-regulated levels of CILP/NTPPH expression were higher in adult chondrocytes than in young chondrocytes. CONCLUSION: These results provide evidence that CILP/NTPPH expression and ePPi elaboration are concomitantly stimulated by TGFbeta1 and down-regulated by IGF-1, especially in adult chondrocytes, implicating CILP/NTPPH as a functional participant in ePPi elaboration. Increased CILP/NTPPH mRNA expression in chondrocytes derived from aged animals compared with young animals might promote the formation of calcium pyrophosphate dihydrate crystals in aged cartilage.

Aging↗
PubMed2000

A meta-analysis of case-control and cohort studies with interval-censored exposure data: application to chorionic villus sampling.

Chorionic villus sampling (CVS) is a valued method of prenatal diagnosis that is often preferred over amniocentesis because it can be performed earlier, but which has also raised concern over a possible association with increased risk of terminal transverse limb deficiency (TTLD). We present and apply a meta-analytic method for estimating a combined dose-response effect from a series of case-control and cohort studies in which the exposure variable is interval-censored. Assuming coarsening at random for the interval-censoring, and calling upon the familiar result of Cornfield to pool case-control and cohort information on the association between a rare binary outcome and a multilevel exposure variable, we form a likelihood-based model to assess the effect of gestational age at the time of CVS on the presence or absence of a rare birth defect. Effect estimates are computed with a variant of the EM algorithm termed the method of weights, which enables the use of standard weighted regression software. Our findings suggest that CVS exposure at early gestational age leads to an increased risk of TTLD.

Journal Article↗
PubMed2000

Generalized additive distributed lag models: quantifying mortality displacement.

There are a number of applied settings where a response is measured repeatedly over time, and the impact of a stimulus at one time is distributed over several subsequent response measures. In the motivating application the stimulus is an air pollutant such as airborne particulate matter and the response is mortality. However, several other variables (e.g. daily temperature) impact the response in a possibly non-linear fashion. To quantify the effect of the stimulus in the presence of covariate data we combine two established regression techniques: generalized additive models and distributed lag models. Generalized additive models extend multiple linear regression by allowing for continuous covariates to be modeled as smooth, but otherwise unspecified, functions. Distributed lag models aim to relate the outcome variable to lagged values of a time-dependent predictor in a parsimonious fashion. The resultant, which we call generalized additive distributed lag models, are seen to effectively quantify the so-called 'mortality displacement effect' in environmental epidemiology, as illustrated through air pollution/mortality data from Milan, Italy.

Journal Article↗