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G B Smith

Publications and source records attributed to G B Smith.

At least 19 recordsLinked to original sources
PubMed2005

The use of routine laboratory data to predict in-hospital death in medical admissions.

The ability to predict clinical outcomes in the early phase of a patient's hospital admission could facilitate the optimal use of resources, might allow focused surveillance of high-risk patients and might permit early therapy. We investigated the hypothesis that the risk of in-hospital death of general medical patients can be modelled using a small number of commonly used laboratory and administrative items available within the first few hours of hospital admission. Matched administrative and laboratory data from 9497 adult hospital discharges, with a hospital discharge specialty of general medicine, were divided into two subsets. The dataset was split into a single development set, Q(1) (n=2257), and three validation sets, Q(2), Q(3) and Q(4) (n(1)=2335, n(2)=2361, n(3)=2544). Hospital outcome (survival/non-survival) was obtained for all discharges. An outcome model was constructed from binary logistic regression of the development set data. The goodness-of-fit of the model for the validation sets was tested using receiver-operating characteristics curves (c-index) and Hosmer-Lemeshow statistics. Application of the model to the validation sets produced c-indices of 0.779 (Q(2)), 0.764 (Q(3)) and 0.757 (Q(4)), respectively, indicating good discrimination. Hosmer-Lemeshow analysis gave chi(2)=9.43 (Q(2)), chi(2)=7.39 (Q(3)) and chi(2)=8.00 (Q(4)) (p-values of 0.307, 0.495 and 0.433) for 8 degrees of freedom, indicating good calibration. The finding that the risk of hospital death can be predicted with routinely available data very early on after hospital admission has several potential uses. It raises the possibility that the surveillance and treatment of patients might be categorised by risk assessment means. Such a system might also be used to assess clinical performance, to evaluate the benefits of introducing acute care interventions or to investigate differences between acute care systems.

Adult↗
PubMed2005

Measuring clinical performance using routinely collected clinical data.

Following the well-publicized problems with paediatric cardiac surgery at the Bristol Royal Infirmary, there is wide public interest in measures of hospital performance. The Kennedy report on the BRI events suggested that such measures should be meaningful to the public, case-mix-adjusted, and based on data collected as part of routine clinical care. We have found that it is possible to predict in-hospital mortality (a measure readily understood by the public) using simple routine data-age, mode of admission, sex, and routine blood test results. The clinical data items can be obtained at a single venesection, are commonly collected in the routine care of patients, are already stored on hospital core IT systems, and so place no extra burden on the clinical staff providing care. Such risk models could provide a metric for use in evidence-based clinical performance management. National application is logistically feasible.

Cardiology Service, Hospital↗
PubMed2002

The impact of low-risk intensive care unit admissions on mortality probabilities by SAPS II, APACHE II and APACHE III.

A large proportion of intensive care unit patients are low-risk admissions. Mortality probabilities generated by predictive systems may not accurately reflect the mortality experienced by subpopulations of critically ill patients. We prospectively assessed the impact of low-risk admissions (mortality risk < 10%) on the mortality estimates generated by three prognostic models. We studied 1497 consecutive admissions to a general intensive care unit. The performance of the three models for subgroups and the whole population was analysed. The proportions of patients designated as low risk varied with the model and differences in model performance were most pronounced for these patients. The APACHE II mortality ratios (1.32 vs. 1.19) did not differ for low- and higher risk patients, but mortality ratios generated by APACHE III (2.38 vs. 1.23) and SAPS II (2.19 vs. 1.16) were nearly two-fold greater. Calibration for higher risk patients was similar for all three models but the APACHE III system calibrated worse than the other models for low-risk patients. This may have contributed to the poorer overall calibration of the APACHE III system (Hosmer-Lemeshow C-test: APACHE III chi(2) = 329; APACHE II chi(2) = 42; SAPS II chi(2) = 62). Imperfect characterisation of the large proportion of low-risk intensive care unit admissions may contribute to the deterioration of the models' predictive accuracies for the intensive care population as a whole.

APACHE↗
PubMed2002

The effects of two methods for customising the original SAPS II model for intensive care patients from South England.

Model customisation is used to adjust prognostic models by re-calibrating them to obtain more reliable mortality estimates. We used two methods for customising the Simplified Acute Physiology Score II model for 15,511 intensive care patients by altering the logit and the coefficients of the original equation. Both methods significantly improved model calibration, but customising the coefficients was slightly more effective. The Hosmer-Lemeshow chi(2)-value improved from 306.0 (p< 0.001) before, to 14.5 (p < 0.07) and 23.3 (p < 0.06) after customisation of the coefficients and the logit, respectively. Discrimination was not affected. The standardised mortality ratio for the entire population declined from 1.16 (95% confidence interval: 1.13-1.20, p < 0.001) to 0.99 (95% confidence interval: 0.96-1.02, p < 0.22) after customisation of the coefficients. The uniformity-of-fit for patients grouped by operative status and comorbidities also improved, but remained imperfect for patients stratified by location before intensive care unit admission. Amalgamation of large, regional databases could provide the basis for the re-calibration of standard prognostic models, which could then be used as a national reference system to allow more reliable comparisons of the efficacy and quality of care based on severity adjusted outcome measures.

Adolescent↗
PubMed2001

Multicenter study of obstetric admissions to 14 intensive care units in southern England.

OBJECTIVES: To identify pregnant and postpartum patients admitted to intensive care units (ICUs), the cause for their admission, and the proportion that might be appropriately managed in a high-dependency environment (HDU) by using an existing database. To estimate the goodness-of-fit for the Simplified Acute Physiology Score II, the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the APACHE III scoring systems in the obstetrical population. DESIGN: Retrospective analysis of demographic, diagnostic, treatment, and severity of illness data. SETTING: Fourteen ICUs in Southern England. PATIENTS: Pregnant or postpartum (<42 days) admissions between January 1, 1994, and December 31, 1996. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 210 patients, constituting 1.84% (210 of 11,385) of all ICU admissions and 0.17% (210 of 122,850) of all deliveries. Most admissions followed postpartum complications (hypertensive disease of pregnancy [39.5%] and major hemorrhage [33.3%]). Seven women were transferred to specialist ICUs. There was considerable variation between ICUs with respect to the number and type of interventions required by patients. Some 35.7% of patients stayed in ICU for <2 days and received no specific ICU interventions; these patients might have been safely managed in an HDU. There were seven maternal deaths (3.3%); fetal mortality rate was 20%. The area under the receiver operator characteristic curve and the standardized mortality ratio were 0.92 (confidence interval [CI], 0.85-0.99) and 0.43 for the Simplified Acute Physiology Score II, 0.94 (CI, 0.86-1.0) and 0.24 for APACHE II, and 0.98 (CI, 0.96-1.0) and 0.43 for APACHE III, respectively. CONCLUSIONS: Existing databases can both identify critically ill obstetrical patients and provide important information about them. Obstetrical ICU admissions often require minimal intervention and are associated with low mortality rates. Many might be more appropriately managed in an HDU. The commonly used severity of illness scoring systems are good discriminators of outcome from intensive care admission in this group but may overestimate mortality rates. Severity of illness scoring systems may require modification in obstetrical patients to adjust for the normal physiologic responses to pregnancy.

APACHE↗
PubMed2001

Human lung microsomal cytochrome P4501A1 (CYP1A1) activities: impact of smoking status and CYP1A1, aryl hydrocarbon receptor, and glutathione S-transferase M1 genetic polymorphisms.

There are numerous conflicting epidemiological studies addressing correlations between cytochrome P450 1A1 (CYP1A1) genetic polymorphisms and lung cancer susceptibility, with associations plausibly linked to alterations in carcinogen bioactivation. Similarly, correlations between aryl hydrocarbon receptor gene (AHR) codon 554 genotype and CYP1A1 inducibility are controversial. The objective of this study was to determine whether smoking status, and CYP1A1, AHR, and glutathione S-transferase M1 gene (GSTM1) polymorphisms correlate with altered CYP1A1 activities. Lung microsomal CYP1A1-catalyzed 7-ethoxyresorufin O-dealkylation (EROD) activities were much higher in tissues from current smokers (n = 46) than in those from non-/former smokers (n = 24; 12.11 +/- 13.46 and 0.77 +/- 1.74 pmol/min/mg protein, respectively, mean +/- SD; P < 0.05). However, EROD activities in lung microsomes from current smokers CYP1A1*1/1 (n = 33) and heterozygous MspI variant CYP1A1*1/2A (n = 10) were not significantly different (12.23 +/- 13.48 and 8.23 +/- 9.76 pmol/min/mg protein, respectively, P > 0.05). Three current smokers were heterozygous variant CYP1A1*1/2B (possessing both *2A and *2C alleles), and exhibited activities similar to individuals CYP1A*1/1. One current smoker was heterozygous variant CYP1A1*4 and exhibited activities comparable with individuals CYP1A1*1/1 at that locus. EROD activities in microsomes from current smokers AHR(554)Arg/Arg (n = 41) and heterozygous variant AHR(554)Arg/Lys (n = 5) were not significantly different (12.13 +/- 13.56 and 12.01 +/- 14.23 pmol/min/mg protein, respectively; P > 0.05). Furthermore, microsomal EROD activities from current smokers with the GSTM1-null genotype (n = 28) were not significantly different from those (n = 18) carrying at least one copy of GSTM1 (12.61 +/- 14.24 and 11.34 +/- 12.53 pmol/min/mg protein, respectively; P > 0.05). Additionally, when genotypic combinations of CYP1A1, AHR, and GSTM1 were assessed, there were no significant effects on EROD activity. On the basis of microsomal enzyme activities from heterozygotes, CYP1A1*1/2A, CYP1A1*1/2B, CYP1A1*1/4, and AHR(554) Arg/Lys variants do not appear to significantly affect CYP1A1 activities in human lung, and we observed no association between CYP1A1 activity and the GSTM1-null polymorphism.

Adult↗
PubMed2000

Dechlorination of polychlorinated methanes by a sequential methanogenic-denitrifying bioreactor system.

A two-stage bioreactor has been developed to link dechlorination of halogenated methane compounds to the anaerobic processes of methanogenesis and denitrification. A digester methanogenic consortium was shown to dechlorinate chloroform (CF) and carbon tetrachloride (CT) to dichloromethane (DCM), and DCM was then mineralized by an acclimated denitrifying biological activated carbon consortium. Combining these two processes, a sequential methanogenic-denitrifying bioreactor (SMDB) system that completely degraded polychlorinated methanes including CT, CF, and DCM was developed. More than 95% of the added CT and CF was dechlorinated in the methanogenic bioreactor with methanol as the primary substrate, and the resultant DCM was biodegraded in the denitrifying bioreactor with nitrate as the electron acceptor. In the denitrifying bioreactor, the residual CF was completely removed, and the DCM removal efficiency was more than 95%. This novel bioreactor system eliminates the need for aeration and so avoids the air contamination associated with aerobic biotreatment of volatile chlorinated pollutants. This SMDB system provides an alternative to conventional biotreatment of wastewaters and other matrices contaminated with polychlorinated methanes and is, to our knowledge, the first report on such a sequential anoxic system.

Bacteria↗
PubMed2000

Deduction of amino acid residues in the GABA(A) receptor alpha subunits photoaffinity labeled with the benzodiazepine flunitrazepam.

Peptide mapping and microsequencing were used to infer the site of photoaffinity labeling by the gamma-aminobutyric acidA receptor modulator [3H]flunitrazepam. Peptide mapping with and without N-deglycosylation was used to restrict the domain for photoaffinity labeling to residues 74-123 of the bovine alpha1 subunit, in agreement with a previously predicted labeling domain between residues 59-148 based on cyanogen bromide fragmentation. Edman degradation of partially purified photolabeled peptides gave release of 3H counts in the ninth cycle of a tryptic peptide sequence. A second V8/chymotryptic peptide produced an impure sequence with release of 3H counts in the seventh through ninth cycle of sequence. The combined data support those previously reported, i.e., that the primary site for photoaffinity labeling by [3H]flunitrazepam is His102 of the bovine alpha1 subunit. In addition we also detected possible secondary labeling of Pro97.

Affinity Labels↗
PubMed2000

Evaluation of behavioral disinhibition in P/NP and HAD1/LAD1 rats.

1. Two lines of rats specifically bred for alcohol preference were exposed to two different behavioral tasks that required behavioral inhibition to successfully solve. 2. Learning and performance of a step-down passive avoidance task and a differential reinforcement of low-rate responding task were studied in P/NP and HAD1/LAD1 rats. 3. While the P rats had difficulty in learning both tasks, HAD1, LAD1 and NP rats performed at control levels. 4. These data suggest that P rats, but not HAD1 rats, may have problems learning tasks that require inhibition of ongoing or previously learned behaviors.

Animals↗
PubMed2000

Mechanisms of aflatoxin B1 lung tumorigenesis.

Although aflatoxin B1 (AFB1) is best known as a hepatocarcinogen, the respiratory system can also be a target of this mycotoxin. In isolated lung cells from rabbits and mice, AFB1 is bioactivated by cytochromes P450, primarily in nonciliated bronchiolar epithelial (Clara) cells. However, mutagenesis experiments suggest that the DNA-binding AFB1 epoxide metabolite can leave the cells of origin, and potentially interact with other cell types. Consistent with DNA adduct studies, AFB1-induced AC3F1 mouse lung tumors contain point mutations at guanine residues in K-ras, with the anticipated bias for the A/J allele. Furthermore, following AFB1 treatment but prior to tumor development, K-ras mutations occur preferentially in mouse Clara cells. However, in contrast to findings with other carcinogens, AFB1-induced mouse lung tumors demonstrate frequent, but heterogeneously distributed, overexpression of p53 protein as well as p53 point mutations, suggesting a carcinogen-specific response. Unlike lung tissue from mice and rabbits, human peripheral lung bioactivates AFB1 primarily by prostaglandin H synthase--and/or lipoxygenase-catalyzed cooxidation, with activity concentrated in macrophages. In addition, although glutathione S-transferase M1-1 has high specific activity for AFB1 epoxide conjugation, lung tissues from GSTM1-null individuals do not demonstrate diminished rates of conjugation, compared to tissues from GSTM1-positive individuals. In summary, AFB1 tumorigenesis in mice demonstrates unique properties, and processes of bioactivation show significant species differences.

Aflatoxin B1↗
PubMed2000

Identification and characterization of nuclease activities in anaerobic environmental samples.

DNA-degrading activity from anaerobic samples of bovine ruminal fluid, primary anaerobic digestor wastewater, freshwater sediments, and marine sediments was observed in the presence of 5 mM EDTA. Nuclease activity experiments involved exposing salmon chromosomal DNA to the environmental samples in 50 mM pH 7.2 buffer, incubating at 37 degrees C, and subjecting the products to electrophoresis. The same stock and concentration of EDTA used in these assays (5 mM) completely inhibited commercial grade DNase. Nuclease activity in two of the samples, ruminal fluid and wastewater, was further characterized. DNA degradation in the ruminal sample was significantly reduced when EDTA or citrate concentrations were increased to 50 mM or above. DNA degradation activity in ruminal fluid was associated with material that passed through a 0.22-micron filter, but wastewater activity was associated with material retained by a 3-micron filter. Degradation activity in the wastewater was resistant to heat pretreatment, whereas the rumen activity was heat-labile (70 degrees C, 60 min). These results demonstrated the biochemical complexity of these two environments and that high molecular weight DNA has a short half-life in these anaerobic environments.

Anaerobiosis↗
PubMed1999

Glutathione S-transferase-catalyzed conjugation of bioactivated aflatoxin B(1) in human lung: differential cellular distribution and lack of significance of the GSTM1 genetic polymorphism.

Epidemiological studies suggest that aflatoxin B(1) (AFB(1)), a mycotoxin produced by certain Aspergillus species, may play a role in human respiratory cancers in occupationally-exposed individuals. AFB(1) requires bioactivation to the corresponding exo-8,9-epoxide for carcinogenicity, and glutathione S-transferase (GST)-catalyzed conjugation of the epoxide with glutathione (GSH) is a critical determinant of susceptibility to AFB(1). Of the purified human GST enzymes studied, the polymorphic hGSTM1-1 has the highest activity towards AFB(1) exo-epoxide. The influence of the GSTM1 polymorphism on AFB(1)-GSH formation, as well as the abilities of cytosols from preparations enriched in different isolated lung cell types to conjugate AFB(1)-epoxides, were examined. In whole-lung cytosols from patients undergoing clinically indicated lobectomy, GSTM1 genotype correlated with GSTM1 phenotype as determined by [(3)H]trans-stilbene oxide conjugation: GSTM1-positive = 295 +/- 31 pmol/mg/h (n = 6); GSTM1-negative = 92.8 +/- 23.3 pmol/mg/h (n = 4) (P < 0.05). In contrast, conjugation of microsome-generated [(3)H]AFB(1)-epoxides with GSH was low and variable between patients, and did not correlate with GSTM1 genotype: GSTM1-positive = 11.9 +/- 8.1, 111 +/- 66 and 510 +/- 248 fmol/mg/h (n = 6); GSTM1-negative = 15.3 +/- 16.7, 167 +/- 225 and 540 +/- 618 fmol/mg/h (n = 4) (for 1, 10 and 100 microM [(3)H]AFB(1), respectively). GSH conjugates of AFB(1) exo-epoxide and the much less mutagenic stereoisomer AFB(1) endo-epoxide were produced in a ratio of approximately 1:1 in cytosols from both whole lung and isolated cells. Total cytosolic AFB(1)-epoxide conjugation was significantly higher in fractions enriched in alveolar type II cells (3.07 +/- 1.61 pmol/mg/h) than in unseparated lung cells (0.143 +/- 0.055 pmol/mg/h) or fractions enriched in alveolar macrophages (0. 904 +/- 0.319 pmol/mg/h; n = 4) (P < 0.05). Furthermore, AFB(1)-GSH formation and percentage of alveolar type II cells in different cell fractions were correlated (r = 0.78, P < 0.05). These results demonstrate that human lung GSTs exhibit very low conjugation activity for both AFB(1)-8,9-epoxide stereoisomers, and that this activity is heterogeneously distributed among cell types, with alveolar type II cells exhibiting relatively high activity. Of the GSTs present in human peripheral lung which contribute to AFB(1) exo- and endo-epoxide detoxification, hGSTM1-1 appears to play at most only a minor role.

Aflatoxin B1↗
PubMed1999

Biotransformation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in freshly isolated human lung cells.

Metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was characterized in human lung cells isolated from peripheral lung specimens obtained from 12 subjects during clinically indicated lobectomy. NNK biotransformation was assessed in preparations of isolated unseparated cells (cell digest), as well as in preparations enriched in alveolar type II cells, and alveolar macrophages. Metabolite formation was expressed as a percentage of the total recovered radioactivity from [5-(3)H]NNK and its metabolites per 10(6) cells per 24 h. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was the major metabolite formed in all lung cell preparations examined, and its formation ranged from 0.50 to 13%/10(6) cells/24 h. Formation of alpha-carbon hydroxylation end-point metabolites (bioactivation) and pyridine N-oxidation metabolites (detoxification), ranged from non-detectable to 0.60% and from non-detectable to 1.5%/10(6) cells/24 h, respectively, reflecting a large degree of intercellular and inter-individual variability in NNK metabolism. Formation of the alpha-hydroxylation end-point metabolite 4-hydroxy-1-(3-pyridyl)-1-butanol (diol) was consistently higher in alveolar type II cells than in cell digest or alveolar macrophages (0.0146 +/- 0.0152, 0.0027 +/- 0.0037 and 0.0047 +/- 0.0063%/10(6) cells/24 h, respectively; n = 12; P < 0.05). SKF-525A was used to examine cytochrome P450 contributions to the biotransformation of NNK. SKF-525A inhibited keto reduction of NNK to NNAL by 85, 86 and 74% in cell digest, type II cells, and macrophages, respectively (means of 11 subjects, P < 0.05). Type II cell incubates treated with SKF-525A formed significantly lower amounts of total alpha-hydroxylation metabolites compared with type II cells without SKF-525A (0.0776 +/- 0.0841 versus 0.1694 +/- 0. 2148%/10(6) cells/24 h, respectively; n = 11; P < 0.05). The results of this first study examining NNK biotransformation in freshly isolated human lung cells indicate that NNK metabolism is subject to a large degree of inter-individual and intercellular variability, and suggest a role for P450s in human lung cell NNK metabolism. Both alveolar type II cells and alveolar macrophages may be potential target cells for NNK toxicity based on their alpha-carbon hydroxylation capabilities. In addition, carbonyl reduction of NNK to NNAL is SKF-525A sensitive in human lung cells.

Aged↗