Biomedical subjects

H Xia

Publications and source records attributed to H Xia.

At least 55 records · Page 3Linked to original sources

PubMed1999

Lung hypoplasia caused by nitrofen is mediated by down-regulation of thyroid transcription factor TTF-1.

Prenatal exposure to nitrofen induces lung hypoplasia and diaphragmatic hernias very similar to those in human disease, but the mechanisms are still unknown. Thyroid transcription factor 1 (TTF-1) is involved in lung ontogeny and regulation of the expression of surfactant proteins, and is likely abnormally expressed in nitrofen-induced lung hypoplasia. This study examines the effect of nitrofen on TTF-1 messenger RNA (mRNA) expression in the lungs of prenatal rat fetuses and a human lung-cell line (NCI-H441) that expresses both TTF-1 and surfactant proteins in vivo. Lungs from preterm fetuses harvested from rats with 100 mg nitrofen on gestational day 9.5 and NCI-H441 cells maintained in RPMI medium containing 10% fetal bovine serum and exposed to nitrofen for different times and concentrations were assayed for TTF-1 mRNA by northern blot analysis. mRNA for TTF-1 was decreased in nitrofen-exposed pups in comparison with controls, and exposure to nitrofen caused a dose- and time-related decrease in TTF-1 expression in H441 cell cultures. These results indicate that nitrofen downregulates TTF-1 both in vivo and in vitro. Since this interferes with lung development, it is reasonable to accept that lung hypoplasia in this model is in part due to the direct effect of the teratogen rather than to compression by the abdominal viscera herniated into the thorax. This mechanism should be explored in the clinical setting.

Animals↗

PubMed1999

Cardiovascular malformations in congenital diaphragmatic hernia: human and experimental studies.

BACKGROUND/PURPOSE: Cardiovascular malformations (CVM) associated with congenital diaphragmatic hernia (CDH) account in part for the high mortality caused by this defect. The aim of this study is to examine the nature of these malformations in a large series of autopsies and to assess if similar defects are also present in rat fetuses with experimental CDH. METHODS: The incidence of CVM and their nature were examined in the autopsy records of 136 stillborns and neonates with CDH admitted to our institution in the last 30 years. Experimental CDH was induced in rat fetuses by giving 100 mg of nitrofen to their mothers on gestational day 9.5, and the fetuses were harvested on day 21 (near full term). The presence of CDH and the anatomy of the heart and great vessels were studied under dissecting microscope after formalin fixation. Unexposed fetuses were used as controls. RESULTS: Thirty-three newborns with CDH (24%) had CVM, either isolated or associated with other defects, and 7 had heart hypoplasia. Most CVM (ventricular septal defect, tetralogy of Fallot, transposition of the great vessels, double-outlet right ventricle) involved the outflow tract. In our animal experiments, no malformations were found in 21 control pups. Conversely, 80 of 130 nitrofen-exposed fetuses (61%) had CDH, and 59 of them (74%) had CVM. A significant association (Fisher's Exact test, P<.01) was found between CDH and CVM because only 25 of the 50 exposed animals without CDH (50%) had CVM. Again, most defects involved the outflow tract and were similar to those seen in human CDH (tetralogy of Fallot, persistent truncus, ventricular septal defect, double-outlet right ventricle, aberrant right subclavian artery, agenetic ductus, and interrupted aortic arch). Animals with CDH had significantly decreased heart weight to fetal weight ratio in comparison with controls and with those without CDH. CONCLUSIONS: The similar nature of the cardiovascular defects found in babies succumbing to CDH and in nitrofen-exposed rats suggests that a similar disturbance of the regional organogenesis related to the neural crest might be involved in both settings, and further validates the use of this animal model for clarifying the cellular and molecular pathogenetic mechanisms.

Animals↗

PubMed1999

Skeletal malformations associated with esophageal atresia: clinical and experimental studies.

BACKGROUND/PURPOSE: Patients with esophageal atresia (EA) often have skeletal malformations. The purpose of this study is to examine if similar defects occur in rat fetuses prenatally exposed to Adriamycin, a chemical capable of causing EA in these animals. METHODS: The charts of 443 babies with EA were reviewed to assess the incidence and nature of these defects in them. Time-mated female rats were given either 2 mg/kg intraperitoneal Adriamycin (experimental group, n = 16) or no treatment (control group, n = 4) on gestational days 8 and 9, and the fetuses were removed near term. Skeletal anatomy was studied after alcian blue and alizarin red staining. RESULTS: A total of 528 skeletal malformations, mainly abnormal segmentation and vertebral identity (extra or defective bodies or ribs), mishaped vertebral bodies, and limb malformations like radial aplasia or hypoplasia were found in 245 babies (55%). Costal fusion and sternal anomalies were present in 17 and 4 babies, respectively. In the animal study, all control fetuses were normal, whereas 83 of 134 experimental fetuses (62%) had EA accompanied by other malformations. No segmentation or vertebral identity anomalies were seen, but butterfly, wedged, and asymmetric vertebral bodies were found at various levels in all animals with EA and in about half of those without it. Three fetuses had rib anomalies, and 3 more had sternal malformations. Ossification of limbs was delayed in treated fetuses and short, thick, and crooked bones were seen in 4 of 31 fetuses with EA and in none of the Adriamycin-exposed ones without EA. CONCLUSIONS: Adriamycin exposure induces in fetal rats, in addition to esophageal, duodenal, and anorectal atresias, high proportions of vertebral malformations and some limb defects of nature not identical but quite similar to that of babies with EA. This further validates this model for investigating the nature of the processes leading to EA and its associated malformations.

Animals↗

PubMed1999

Tracheobronchial malformations in experimental esophageal atresia.

BACKGROUND: Malformations of the tracheobronchial tree may account for postoperative respiratory symptoms in patients with esophageal atresia (EA). This study examines the respiratory tract in fetal rats with EA induced by Adriamycin. METHODS: Time-mated female rats were given either 2 mg/kg intraperitoneal Adriamycin on gestational days 8 and 9 (adria group, n = 6) or no treatment (control group, n = 2), and the fetuses were recovered on day 21. Laryngo-tracheo bronchial tree was studied after transparentation and alcian blue-alizarin red staining that depicts the cartilage in blue and make the surrounding tissues transparent. RESULTS: There were no malformations in any of the 1 1 control animals studied. Conversely, 31 of 46 (67%) Adriamycin fetuses had EA with distal TEF. These had more tracheal rings than controls (32+/-2 v 26+/-1.5, P < .05) at the expense of those of the mainstem bronchi (3.2+/-1 v 6.6+/-1.1 in the right, P< .05 and 6.2+/-2.1 v 11+/-1.1 in the left, P < .05). There were tracheal stenoses in 16 pups with EA (some severe and five double), and all these had fragmented rings in the trachea or bronchi. In six cases there was an ectopic upper right bronchus, and 1 had a grossly abnormal larynx. The malformations in the 15 Adriamycin-exposed fetuses without EA were limited to some fragmented or mishaped rings. CONCLUSIONS: Laryngo-tracheobronchial malformations entailing the whole length of the tract are very constant and severe in rats with EA and tracheoesophageal fistula and correspond to an abnormal development of the tracheobronchial anlage from the ventral foregut. Their nature and extent invite a careful investigation of the respiratory tracts in EA babies in whom they could be underscored.

Abnormalities, Drug-Induced↗

PubMed1999

Heart hypoplasia in experimental congenital diaphragmatic hernia.

BACKGROUND/PURPOSE: Heart hypoplasia is associated with congenital diaphragmatic hernia (CDH) and decisively influences survival rate. This study examines whether nitrofen-exposed fetal rats have heart hypoplasia. METHODS: Pregnant rats received either 100 mg nitrofen or vehicle on gestational day 9.5. The hearts recovered near full term were either formalin fixed for anatomic studies or snap-frozen for biochemical studies. Heart weight, ventricular chamber diameters and aortic-to-pulmonary root diameter ratios were measured in fixed hearts. Protein and DNA were determined in frozen hearts. Analysis of variance (ANOVA) and correlation-regression studies were used for statistical assessment. RESULTS: All control fetuses were normal, whereas 61% of those exposed to nitrofen had CDH. Cardiovascular malformations were found in 73% of CDH and in 50% of non-CDH animals. Wet and fixed heart weights in percent of fetal weight, left-to-right ventricular diameter ratio, and aortic-to-pulmonary root diameter ratio were significantly decreased in fetuses with CDH in comparison with controls. Only wet heart was significantly decreased in nitrofen-treated fetuses without CDH, although all other variables showed a trend in the same direction. Protein to DNA ratios were similar in the three groups. The structure of the myocytes was histologically similar in all groups. CONCLUSIONS: The spectrum of lesions in the nitrofen model of CDH encompasses heart hypoplasia, further validating its use for research on this condition. Heart hypoplasia is related to cardiopulmonary compression, but its presence in treated animals without CDH demonstrates that the teratogen itself participate directly in its pathogenesis, and this finding invites further research on this line.

Analysis of Variance↗

PubMed1999

Skeletal malformations associated with congenital diaphragmatic hernia: experimental and human studies.

BACKGROUND/PURPOSE: Skeletal malformations are seen occasionally in infants with congenital diaphragmatic hernia (CDH). This study examines whether nitrofen, able to produce CDH in fetal rats, also induces skeletal anomalies and, if so, whether these are similar to those seen in CDH patients. METHODS: Pregnant rats received either nitrofen (100 mg, n = 7) or no treatment (n = 2) on gestational day 9.5. Skeletal anatomy was studied in fetuses recovered on day 21 after alcian blue-alizarin red staining. The charts and postmortem records of 117 stillborns or newborns who died of CDH were investigated retrospectively for skeletal defects. The proportions of anomalies found in the different groups were compared. RESULTS: The 15 control rat fetuses were normal, whereas 57 of 90 nitrofen-exposed animals (63%) had CDH accompanied by other malformations. Skeletal defects limited to vertebral segmentation or identity anomalies (split vertebra or absent, hypoplastic, or fused ribs) were seen at low thoracic and high lumbar levels in 68% of animals with CDH and in 57% of those without. Delayed ossification of limbs was seen in treated animals. There were skeletal malformations in 31.6% of the 117 human patients with CDH. Costovertebral defects (malformed, extra or defective vertebral bodies or ribs and spina bifida) were comparably frequent in infants with syndromes and in those without them (31.2% v 17.8%, not significant), whereas limb defects were significantly more frequent in those with syndromes (56.2% v 13.9%, P<.05). CONCLUSION: The nature and location of costovertebral malformations found in both CDH patients and nitrofen-exposed rats suggest that the diaphragmatic defect and the associated organ malformations might be caused by the same early embryonal disturbance involving axial and para-axial mesoderm.

Animals↗

PubMed1999

Mortality risks of peritoneal dialysis and hemodialysis.

Studies of outcomes associated with dialysis therapies have yielded conflicting results. Bloembergen et al showed that prevalent patients on continuous ambulatory peritoneal dialysis (CAPD) or continuous cycling peritoneal dialysis (CCPD) had a 19% higher mortality risk than hemodialysis patients, and Fenton et al, analyzing Canadian incident patients, found a 27% lower risk. Attempting to reconcile these differences, we evaluated incident Medicare patients (99,048 on hemodialysis, 18,110 on CAPD/CCPD) from 1994 through 1996, following up to June 30, 1997. Patients were followed to transplantation, death, loss to follow-up, 60 days after modality change, or end of the study period. For each 3-month survival period, we used an interval Poisson regression to compare death rates, adjusting for age, gender, race, and primary renal diagnosis. A Cox regression was used to evaluate cause-specific mortality, and proportionality was addressed in both regressions by separating diabetic and nondiabetic patients. The Poisson regressions showed CAPD/CCPD to have outcomes comparable with or significantly better than hemodialysis, although results varied over time. The Cox regression found a lower mortality risk in nondiabetic CAPD/CCPD patients (women younger than 55 years: risk ratio [RR] = 0. 61; Cl, 0.59 to 0.66; women age 55 years or older: RR = 0.87; Cl, 0. 84 to 0.91; men younger than 55 years: RR = 0.72; Cl, 0.67 to 0.77; men age 55 years or older: RR = 0.87; Cl, 0.83 to 0.92) and in diabetic CAPD/CCPD patients younger than 55 (women: RR = 0.88; Cl, 0. 82 to 0.94; men: RR = 0.86; Cl, 0.81 to 0.92). The risk of all-cause death for female diabetics 55 years of age and older, in contrast, was 1.21 (Cl, 1.17 to 1.24) for CAPD/CCPD, and in cause-specific analyses, these patients had a significantly higher risk of infectious death. We conclude that, overall, within the first 2 years of therapy, short-term CAPD/CCPD appears to be associated with superior outcomes compared with hemodialysis. It also appears that patients on the two therapies have different mortality patterns over time, a nonproportionality that makes survival analyses vulnerable to the length of follow-up. Further investigation is needed to evaluate both the potential explanations for these findings and the use of more advanced statistical methods in the analysis of mortality rates associated with these dialytic therapies.

Aged↗

PubMed1999

Role of AMPA receptor cycling in synaptic transmission and plasticity.

Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs). Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the subsequent induction of LTD. These results suggest that AMPARs, but not NMDARs, cycle into and out of the synaptic membrane at a rapid rate and that certain forms of synaptic plasticity may utilize this dynamic process.

Animals↗

PubMed1999

Specificity of murine glutathione S-transferase isozymes in the glutathione conjugation of (-)-anti- and (+)-syn-stereoisomers of benzo[g]chrysene 11,12-diol 13,14-epoxide.

Specificities of murine glutathione (GSH) S-transferase (GST) isozymes mGSTA1-1, mGSTA2-2, mGSTA3-3 and mGSTA4-4 (alpha class), mGSTP1-1 (pi class) and mGSTM1-1 (mu class) for GSH conjugation of (-)-anti- and (+)-syn-stereoisomers of benzo[g]chrysene 11, 12-diol 13,14-epoxide (B[g]CDE), the activated metabolites of the environmental pollutant benzo[g]chrysene (B[g]C), have been determined. When GST activity was determined as a function of varying (-)-anti- or (+)-syn-B[g]CDE concentration (10-320 microM) at a fixed saturating concentration of GSH (2 mM), each isozyme obeyed Michaelis-Menten kinetics. mGSTA1-1 was significantly more efficient than other murine GSTs in the GSH conjugation of not only (-)-anti-stereoisomer but also (+)-syn-B[g]CDE. For example, the catalytic efficiency (k(cat)/K(m)) of mGSTA1-1 towards (-)-anti-B[g]CDE was approximately 2.3- to 16.6-fold higher compared with other murine GSTs. Likewise, mGSTA1-1 was approximately 2.7-, 6.7-, 4.4- and 12.4-fold more efficient than mGSTA2-2, mGSTA3-3, mGSTP1-1 and mGSTM1-1, respectively, in catalyzing the GSH conjugation of (+)-syn-B[g]CDE. Interestingly, mGSTA4-4, which also belongs to class alpha, was virtually inactive towards both stereoisomers of B[g]CDE. The results of the present study indicate that murine GSTs, especially alpha class isozymes, significantly differ in their ability to detoxify B[g]CDE stereoisomers and that mGSTA1-1 plays a major role in the detoxification of both (-)-anti- and (+)-syn-B[g]CDE, which among four B[g]CDE stereoisomers are formed from the carcinogen B[g]C as major DNA binding metabolites.

Animals↗

PubMed1999

Hematocrit level and associated mortality in hemodialysis patients.

Although a number of clinical studies have shown that increased hematocrits are associated with improved outcomes in terms of cognitive function, reduced left ventricular hypertrophy, increased exercise tolerance, and improved quality of life, the optimal hematocrit level associated with survival has yet to be determined. The association between hematocrit levels and patient mortality was retrospectively studied in a prevalent Medicare hemodialysis cohort on a national scale. All patients survived a 6-mo entry period during which their hematocrit levels were assessed, from July 1 through December 31, 1993, with follow-up from January 1 through December 31, 1994. Patient comorbid conditions relative to clinical events and severity of disease were determined from Medicare claims data and correlated with the entry period hematocrit level. After adjusting for medical diseases, our results showed that patients with hematocrit levels less than 30% had significantly higher risk of all-cause (12 to 33%) and cause-specific death, compared to patients with hematocrits in the 30% to less than 33% range. Without severity of disease adjustment, patients with hematocrit levels of 33% to less than 36% appear to have the lowest risk for all-cause and cardiac mortality. After adjusting for severity of disease, the impact of hematocrit levels of 33% to less than 36% is vulnerable to the patient sample size but also demonstrates a further 4% reduced risk of death. Overall, these findings suggest that sustained increases in hematocrit levels are associated with improved patient survival.

Adult↗

PubMed1999

Hematocrit levels and hospitalization risks in hemodialysis patients.

The association between hematocrit level and future hospitalization risks in hemodialysis patients has not been fully investigated on a national level. A total of 71,717 prevalent Medicare hemodialysis patients who survived a 6-mo entry period from July 1 through December 31, 1993 were studied, and their risk of hospitalizations was evaluated the next year. Five hematocrit groups were defined from Medicare recombinant human erythropoietin-treated patients: <27%, 27 to <30%, 30 to <33%, 33 to <36%, and > or =36%. A Cox regression model was used to investigate the association between hematocrit level and the risk of first hospitalization, and the Andersen-Gill regression model evaluated multiple hospitalizations during the next year, adjusting for patient comorbidity and severity of disease. Compared with the baseline group of 30 to <33%, patients with hematocrit levels <30% had a 14 to 30% increased risk of hospitalization without disease severity adjustment (p = 0.0001) and a 7 to 18% increased risk with disease severity adjustment (p = 0.0001). Patients in the 33 to <36% group had the lowest risk at 0.93 and 0.88 (p = 0.0001), with and without adjustment for disease severity. It is concluded that patients with hematocrits of <30% have an increased risk of future hospitalization, with hematocrit levels between 33 and 36% having the lowest associated risks.

Adult↗

PubMed1999

Isolation of cDNAs encoding gibbon and monkey platelet and T cell activation antigen 1 (PTA1).

Human platelet and T cell activation antigen 1 (PTA1) is a 67kDa type I transmembrane glycoprotein mainly expressed on the surface of activated T cells and platelets, and is involved in the development of human cytotoxic T cell (CTL) as well as platelet activation and aggregation. We have cloned and sequenced gibbon PTA1 (gPTA1) and monkey PTA1 (mPTA1) cDNAs by RT-PCR from gibbon leukemic cell line MLA 144 and PHA-induced Rhesus monkey PBMC respectively. The mature proteins of gPTA1, mPTA1 and human PTA1 (hPTA1) share 93-95% amino acid similarity with the highest similarity in domain 1 of extracellular region. All the important features of PTA1 molecule are conserved among these Primates: (1) the ORF encoding 336 amino acid residues including signal sequence (18aa), extracellular region (232aa), transmembrane sequence (25aa) and cytoplasmic region (61aa); (2) two conserved pairs of Cys (Cys19 to Cys90 and Cys134 to Cys204) forming disulfide bonds stabilizing the two immunoglobulin superfamily V-like domains; (3) eight putative N-linked glycosylation sites (except gPTA1 with nine sites) and three O-linked glycosylation sites in extracellular region; and (4) predicated protein kinase C phosphorylation sites (Thr275 and Ser311), casein kinase II sites (Ser295 and The299) and the potential tyrosine phosphorylation site (Tyr304). These data indicate that PTA1 molecule is highly conserved among the Primates and may play important roles in immune response.

Amino Acid Sequence↗

PubMed1999

Transcranial Doppler characteristics in persistent vegetative status, locked-in syndrome and brain death.

AIM: Comparison of the transcranial Doppler (TCD) characteristics of cerebral circulation in persistent vegetative status (PVS), locked-in syndrome and brain death patients. METHODS: Using TCD ultrasound to detect the flow velocity and waveform patterns of middle cerebral artery (MCA) and basilar artery (BA) in patients with PVS, locked-in syndrome and brain death. RESULTS: The mean velocities of middle cerebral artery (Vmca) and basilar artery (Vba) were 30.0 cm/s and 24.3 cm/s in PVS patients respectively, which decreased 45.0% and 14.4% in comparing with normal value. For patients with locked-in syndrome, Vmca and Vba were 49.7 cm/s and 9.8 cm/s, which decreased 5.0% and 61.7% than the normal value respectively. These results showed that the decrease of anterior circulation was predominant in PVS, and the decrease of posterior circulation was predominant in locked-in syndrome. A unique diastolic reverse flow, short peak systolic wave or undetectable flow signal in middle cerebral artery were predominant in brain death patients, which was completely different from that of either PVS or locked-in syndrome. CONCLUSION: TCD was a valuable tool in distinguishing PVS, locked-in syndrome and brain death patients according to the differences in velocities and patterns of anterior and posterior cerebral arteries.

Adolescent↗

PubMed1998

Whole body hyperthermia selectively induces heat shock protein 72 in neurons of the rat spinal cord.

The aims of this study were to examine whether the heat shock response is operative in the spinal cord, and to identify the type of responsible cell. Immunoblot analysis using an antibody specific for a highly stress-inducible heat shock protein with a molecular mass of 72 kDa (HSP72) showed that exposing rats to whole body hyperthermia remarkably induced HSP72 protein in the spinal cord within 2 h. Northern blot analysis with a cDNA probe for human HSP72 demonstrated that whole body hyperthermia induced the expression of HSP72 mRNA within 30 min in the spinal cord. Immunohistochemical analysis showed that neurons in the gray matter appear to be a preferential target of the heat shock response, suggesting that the heat shock response might have a therapeutic implication for protection against spinal cord injury.

Animals↗

PubMed1998

Catalytic efficiencies of allelic variants of human glutathione S-transferase P1-1 toward carcinogenic anti-diol epoxides of benzo[c]phenanthrene and benzo[g]chrysene.

Four allelic variants of glutathione (GSH) S-transferase P1-1 (hGSTP1-1) that differ in their structures at amino acid(s) in position(s) 104 and/or 113 are known to exist in human populations. However, the physiological significance of hGSTP1-1 polymorphism is not fully understood. In this communication, we report that the I104,A113 allele of hGSTP1-1, which is most frequent in human populations, is also most efficient in the GSH conjugation of carcinogenic anti-diol epoxides of benzo[g]chrysene and benzo[c]phenanthrene (anti-BGCDE and anti-BCPDE, respectively). The catalytic efficiency of hGSTP1-1(I104,A113) isoform toward anti-BGCDE, 0.36 mM(-1) x s(-1), was approximately 1.7-fold higher (P < 0.05) compared with hGSTP1-1(V104,V113). Interestingly, the frequency of codon 104-valine alleles is significantly higher in certain cancers compared with codon 104-isoleucine alleles. Like anti-BGCDE, the catalytic efficiency of hGSTP1-1(I104,A113) isoform toward anti-BCPDE was higher by about 1.4- to 2.2-fold (P < 0.05) than those of other hGSTP1-1 variants. These observations are interesting because we have shown previously (Hu, X. et al., Biochem. Biophys. Res. Commun., 238: 397-402, 1997) that the V104,V113 variant, not the I104,A113 isoform, is most efficient in the GSH conjugation of bay-region anti-diol epoxide of benzo(a)pyrene (anti-BPDE), which, unlike anti-BGCDE or anti-BCPDE, is a planar molecule. In conclusion, our results suggest that hGSTP1-1 polymorphism may be an important factor in differential susceptibility of humans to cancers where polycyclic aromatic hydrocarbons are etiological factors and that I104,A113 variant may play a major role in the detoxification of nonplanar, sterically hindered fjord-region diol epoxides (e.g., anti-BGCDE).

Alleles↗

PubMed1998

Differential enantioselectivity of murine glutathione S-transferase isoenzymes in the glutathione conjugation of trans-3,4-dihydroxy-1, 2-oxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene stereoisomers.

The kinetics of the glutathione (GSH) conjugation of (+)- and (-)-enantiomers of anti- as well as syn-3,4-dihydroxy-1,2-oxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene (B[c]PDE) catalyzed by murine GSH S-transferase (GST) isoenzymes has been investigated. Murine GSTs exhibited significant differences in their enantioselectivity toward B[c]PDE stereoisomers. For example, while pi class isoenzyme mGSTP1-1 was virtually inactive toward stereoisomers with 1S configuration [(-)-syn-and (+)-anti-B[c]PDE], these stereoisomers were good substrates for alpha class isoenzyme mGSTA1-2. When GST activity was measured as a function of varying B[c]PDE concentration (10-320 microM) at a fixed saturating concentration of GSH (2 mM), each isoenzyme examined obeyed Michaelis-Menten kinetics with all four B[c]PDE stereoisomers. Alpha class isoenzyme mGSTA4-4 exhibited negligible activity toward all four stereoisomers of B[c]PDE. The catalytic efficiency of mGSTA1-2 was approximately 1.5- to 15-fold higher than other murine GSTs in the GSH conjugation of (-)-anti-B[c]PDE, which among the four B[c]PDE stereoisomers is the most potent pulmonary carcinogen in the newborn mouse model and a potent skin tumor-initiator. While alpha class isoenzymes mGSTA3-3 and mGSTA1-2 were equally efficient in the GSH conjugation of (+)-anti-B[c]PDE, their catalytic efficiencies toward this stereoisomer were significantly higher than those of mGSTP1-1 and mGSTM1-1. Likewise, mGSTA1-2 was relatively more efficient than other GSTs in the GSH conjugation of both enantiomers of syn-B[c]PDE. In summary, our results indicate that (a) murine GSTs significantly differ in their enantioselectivity in the GSH conjugation of B[c]PDE stereoisomers, which may partially account for the observed differences in the carcinogenic potency of B[c]PDE stereoisomers, and (b) mGSTA1-2 and mGSTA3-3 play a major role in the detoxification of B[c]PDE.

Animals↗

PubMed1998

Spatio-temporal models with errors in covariates: mapping Ohio lung cancer mortality.

In estimating spatial disease patterns, as well as in related assessments of environmental equity, regional morbidity and mortality rate maps are widely used. Hierarchical Bayes methods are increasingly popular tools for creating such maps, since they permit smoothing of the fitted rates toward spatially local mean values, with more unreliable estimates (those arising in low-population regions) receiving more smoothing. In this paper we blend methods for spatial-temporal mapping with those for handling errors in covariates in a single hierarchical model framework. Estimated posterior distributions for the resulting highly-parameterized models are obtained via Markov chain Monte Carlo (MCMC) methods, which also play a key role in our approach to model evaluation and selection. We apply our approach to a data set of county-specific lung cancer rates in the state of Ohio during the period 1968-1988. Our model uses age-adjusted death rates, and incorporates recent information regarding smoking prevalence, population density, and the socio-economic status of the counties. This information is critical to understanding the role played by a certain depleted uranium fuel processing facility on the elevated lung cancer rates in the counties that neighbour it.

Adolescent↗

PubMed1998

Dyspepsia in the community is linked to smoking and aspirin use but not to Helicobacter pylori infection.

BACKGROUND: The relationship between Helicobacter pylori infection and symptoms remains controversial. We aimed to determine if an association exists between unexplained dyspepsia (pain or discomfort centered in the upper part of the abdomen) and H pylori. METHODS: A validated questionnaire was completed by 592 healthy blood donors. Helicobacter pylori serologic values (via enzyme-linked immunosorbent assay), blood group status, and Rh status were measured; 4.9% of subjects who had a history of peptic ulcer disease were excluded from the analyses. RESULTS: The prevalence of dyspepsia and no ulcer history was 11% (95% confidence interval [CI], 8.6%-13.8%); 15.4% of subjects with dyspepsia had H pylori while 14.6% of subjects without dyspepsia were infected (P=.90). The mean dyspepsia impact scores (combining frequency and severity) in those with and without H pylori were 4.7 and 5.4, respectively (P=.20). The median H pylori optical density values in dyspepsia vs no dyspepsia were not significantly different (P=.30). Independent risk factors for dyspepsia were the use of aspirin (odds ratio [OR], 2.2; 95% CI, 1.3-3.7) and smoking (OR, 2.1; 95% CI, 1.3-3.6) but not age, sex, marital status, educational level, income, or the use of alcohol, coffee, or nonsteroidal anti-inflammatory drugs. Independent risk factors for H pylori were increasing age (OR, 1.8 per decade; 95% CI, 1.5-2.3), male sex (OR, 2.1; 95% CI, 1.3-3.4), and net family income (OR, 1.8; 95% CI, 1.2-3.3). CONCLUSION: Dyspepsia in the community is linked to smoking and aspirin use, but not to H pylori infection.

Adult↗