Biomedical subjects

H Xia

Publications and source records attributed to H Xia.

At least 19 recordsLinked to original sources

PubMed1999

Dynamin-dependent endocytosis of ionotropic glutamate receptors.

Little is known about the mechanisms that regulate the number of ionotropic glutamate receptors present at excitatory synapses. Herein, we show that GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) are removed from the postsynaptic plasma membrane of cultured hippocampal neurons by rapid, ligand-induced endocytosis. Although endocytosis of AMPARs can be induced by high concentrations of AMPA without concomitant activation of N-methyl-D-aspartate (NMDA) receptors (NMDARs), NMDAR activation is required for detectable endocytosis induced by synaptically released glutamate. Activated AMPARs colocalize with AP2, a marker of endocytic coated pits, and endocytosis of AMPARs is blocked by biochemical inhibition of clathrin-coated pit function or overexpression of a dominant-negative mutant form of dynamin. These results establish that ionotropic receptors are regulated by dynamin-dependent endocytosis and suggest an important role of endocytic membrane trafficking in the postsynaptic modulation of neurotransmission.

Adaptor Protein Complex 2↗

PubMed1999

Metabolic fate of glutathione conjugate of benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide in human liver.

Benzo[a]pyrene-(7R,8S)-diol (9S,10R)-epoxide [(+)-anti-BPDE] is believed to be the activated form of the widely spread environmental pollutant benzo[a]pyrene. Glutathione (GSH) S-transferase (GST)-catalyzed conjugation of (+)-anti-BPDE with GSH is an important mechanism in its cellular detoxification. Here, we report that the GSH conjugate of (+)-anti-BPDE [(-)-anti-BPD-SG] is a potent inhibitor (K(i) 15 microM) of class Mu human GST isoenzyme, which, among human liver GSTs, is a highly efficient detoxifier of (+)-anti-BPDE. Thus, the inhibition of GST activity by (-)-anti-BPD-SG may hinder GSH conjugation of (+)-anti-BPDE, unless the conjugate is metabolized and/or eliminated. The results of the present study show that gamma-glutamyltranspeptidase (gamma-GT) can metabolize (-)-anti-BPD-SG at a rate of about 0.29 nmol/min/mg protein. Our studies also show that (-)-anti-BPD-SG is transported across the human canalicular liver plasma membrane (cLPM) in an ATP-dependent manner at a rate of about 0.33 nmol/min/mg protein. The ATP-dependent transport of (-)-anti-[(3)H]BPD-SG across human cLPM follows Michaelis-Menten kinetics (K(m) 84 microM; V(max) 0.33 nmol/min/mg). In conclusion, the results of the present study suggest that both gamma-GT-mediated metabolism and ATP-dependent canalicular transport may be important steps in overall detoxification of (+)-anti-BPDE in the human liver.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1999

The degradation of nascent fibrinogen chains is mediated by the ubiquitin proteasome pathway.

Recent studies have shown that ubiquitin-dependent proteolysis by proteasomes plays an essential role in the degradation of ER-retained proteins. We investigated the degradation of individual fibrinogen chains in transfected COS cells which express but do not secrete single chains. In transfected COS cells, the degradation of fibrinogen Bbeta and gamma chain was markedly inhibited by the proteasome inhibitors lactacystin and MG132. These specific proteasome inhibitors also partially affected the degradation of Aalpha chain. In HepG2 cells, which synthesize and secrete fibrinogen, the degradation of intracellular free gamma chain was also inhibited by MG132. We also detected high molecular weight polyubiquitinated forms of fibrinogen chains in transfected COS cells and in HepG2 cells by sequential immunoprecipitation. These results implicate proteasomes in the degradation of fibrinogen chains. In COS cells, gamma chains have a longer half-life than Bbeta chains and Aalpha chains, suggesting that the presence of surplus gamma chains in fibrinogen-producing cells is due to the unequal degradation rate of fibrinogen chains. These results indicate that the ubiquitin-proteasome pathway may be a major system for the degradation of unassembled fibrinogen chains.

Acetylcysteine↗

PubMed1999

Amino acid substitutions at positions 207 and 221 contribute to catalytic differences between murine glutathione S-transferase Al-1 and A2-2 toward (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene.

We have previously identified a novel Alpha class murine glutathione (GSH) S-transferase isoenzyme (designated mGSTAl-2) which is exceptionally efficient in catalyzing the GSH conjugation of (+)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], the ultimate carcinogen of widespread environmental pollutant benzo[a]pyrene. Furthermore, we have demonstrated that the Al-type subunit of this isoenzyme is significantly more active toward (+)-anti-BPDE than the other subunit (mGSTA2). To establish the basis for catalytic differences between mGSTAl and mGSTA2, which differ in their primary structures by 10 amino acids [distributed in three sections (I-III) as clusters of two (residues 65 and 95), three (residues 157, 162, and 169), and five (residues 207, 213, 218, 221, and 222) amino acids], three chimeric enzymes were expressed and tested for their activity toward (+)-anti-BPDE. These studies revealed that amino acid substitution(s) in section III determined the high catalytic activity of mGSTAl. Molecular modeling studies suggested that amino acid substitutions at positions 207 and/or 221, but not at positions 213, 218, and 222, may be responsible for such a difference. To test this possibility, amino acids at positions 207 and 221 of mGSTAl were mutated with the equivalent residues of mGSTA2. Kinetic analysis of the wild type and the mutant enzymes revealed that both methionine-207 and isoleucine-221 are critical for higher activity of mGSTA1-1 toward (+)-anti-BPDE compared with that of mGSTA2-2.

Amino Acid Substitution↗

PubMed1999

Human placental Na+-dependent multivitamin transporter. Cloning, functional expression, gene structure, and chromosomal localization.

We have cloned the human Na+-dependent multivitamin transporter (SMVT), which transports the water-soluble vitamins pantothenate, biotin, and lipoate, from a placental choriocarcinoma cell line (JAR). The cDNA codes for a protein of 635 amino acids with 12 transmembrane domains and 4 putative sites for N-linked glycosylation. The human SMVT exhibits a high degree of homology (84% identity and 89% similarity) to the rat counterpart. When expressed in HRPE cells, the cDNA-induced transport process is obligatorily dependent on Na+ and accepts pantothenate, biotin, and lipoate as substrates. The relationship between the cDNA-specific uptake rate of pantothenate or biotin and Na+ concentration is sigmoidal with a Na+:vitamin stoichiometry of 2:1. The human SMVT, when expressed in Xenopus laevis oocytes, induces inward currents in the presence of pantothenate, biotin, and lipoate in a Na+-, concentration-, and potential-dependent manner. We also report here on the structural organization and chromosomal localization of the human SMVT gene. The SMVT gene is approximately 14 kilobase pairs in length and consists of 17 exons. The SMVT gene is located on chromosome 2p23 as evidenced by somatic cell hybrid analysis and fluorescence in situ hybridization.

Amino Acid Sequence↗

PubMed1999

Gender related differences in ATP-dependent transport of dinitrophenyl-glutathione conjugate across murine canalicular liver plasma membrane.

The present study reports gender related differences in ATP-dependent transport of dinitrophenyl-glutathione (GSH) conjugate (DNP-SG), a model GSH xenobiotic conjugate, across murine canalicular liver plasma membrane (cLPM). ATP-dependent transport of DNP-SG across female A/J mouse cLPM was mediated by two components, a high-affinity and a low-affinity component, with corresponding Km of 18 microM (Vmax 0.02 nmol/min.mg) and 500 microM (Vmax 0.23 nmol/min.mg), respectively. On the other hand, only one component for the ATP-dependent transport of DNP-SG was observed in male mouse cLPM (K(m) 130 microM; Vmax 0.18 nmol/min.mg). Moreover, the rate of ATP-dependent transport of DNP-SG was markedly higher in the cLPM fraction of male mouse compared with that of the female. Presence of two transport components in female mouse cLPM, but only one system in the cLPM fraction of male mouse, was confirmed by measuring DNP-SG mediated stimulation of ATP hydrolysis (DNP-SG ATPase activity). To the best of our knowledge, the present study is the first report on gender related differences in ATP-dependent murine canalicular transport of GSH conjugates.

Adenosine Triphosphate↗

PubMed1999

The tracheobronchial tree is abnormal in experimental congenital diaphragmatic hernia.

Neonates with congenital diaphragmatic hernia (CDH) have other malformations that contribute to the high mortality. The nitrofen rat model allows experimental study of these anomalies. This study examines whether the tracheobronchial tree is also abnormal in this model. Time-mated rats received 100 mg nitrofen on gestational day 9. 5; 90 fetuses were harvested on day 21 (near full term) and dissected. The trachea and bronchi were stained with alcian blue-alizarin red and their anatomy was examined by transillumination under a microscope. The findings were compared with those of 11 suitable controls. Control pups had no malformations. Those with CDH (n = 57) had significantly decreased numbers of tracheal rings in comparison with controls (22.9 +/- 1.9 vs 26 +/- 1.9, P < 0.05) and 40/57 had fragmented rings (0 in controls). Twelve CDH animals had, in addition, tracheal stenoses of variable severity, sometimes related to vascular rings. Nitrofen fetuses without CDH (n = 33) had only short tracheas and 4 had mild stenoses. Nitrofen-exposed fetuses have, in addition to lung hypoplasia and sometimes CDH, severe tracheobronchial anomalies that suggest the involvement of pathogenetic mechanisms capable of acting on various tissue components. The genetic control of organogenesis is most probably disturbed by the teratogen.

Animals↗

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↗