Mortality differences and inequalities within and between 'protected characteristics' groups, in a Scottish Cohort 1991-2009.

BACKGROUND: Little is known about the interaction between socio-economic status and 'protected characteristics' in Scotland. This study aimed to examine whether differences in mortality were moderated by interactions with social class or deprivation. The practical value was to pinpoint population groups for priority action on health inequality reduction and health improvement rather than a sole focus on the most deprived socioeconomic groups. METHODS: We used data from the Scottish Longitudinal Study which captures a 5.3 % sample of Scotland and links the censuses of 1991, 2001 and 2011. Hazard ratios for mortality were estimated for those protected characteristics with sufficient deaths using Cox proportional hazards models and through the calculation of European age-standardised mortality rates. Inequality was measured by calculating the Relative Index of Inequality (RII). RESULTS: The Asian population had a polarised distribution across deprivation deciles and was more likely to be in social class I and II. Those reporting disablement were more likely to live in deprived areas, as were those raised Roman Catholic, whilst those raised as Church of Scotland or as 'other Christian' were less likely to. Those aged 35-54 years were the least likely to live in deprived areas and were most likely to be in social class I and II. Males had higher mortality than females, and disabled people had higher mortality than non-disabled people, across all deprivation deciles and social classes. Asian males and females had generally lower mortality hazards than majority ethnic ('White') males and females although the estimates for Asian males and females were imprecise in some social classes and deprivation deciles. Males and females who reported their raised religion as Roman Catholic or reported 'No religion' had generally higher mortality than other groups, although the estimates for 'Other religion' and 'Other Christian' were less precise.Using both the area deprivation and social class distributions for the whole population, relative mortality inequalities were usually greater amongst those who did not report being disabled, Asians and females aged 35-44 years, males by age, and people aged <75 years. The RIIs for the raised religious groups were generally similar or too imprecise to comment on differences. CONCLUSIONS: Mortality in Scotland is higher in the majority population, disabled people, males, those reporting being raised as Roman Catholics or with 'no religion' and lower in Asians, females and other religious groups. Relative inequalities in mortality were lower in disabled than nondisabled people, the majority population, females, and greatest in young adults. From the perspective of intersectionality theory, our results clearly demonstrate the importance of representing multiple identities in research on health inequalities.

In Vitro Biodegradation of Resorbable Magnesium Alloys Promising for Implant Development.

The aim of the investigation was to study the biodegradation characteristics and rate of magnesium alloys in vitro. MATERIALS AND METHODS: We studied the biodegradation of magnesium alloys Mg-Zn-Ca and WE43 (Mg-Y-Nd-Zr) in homogenized (initial) condition and after strengthening by mechanical processing using equal channel angular pressing (ECAP). The samples were incubated in a model system based on reference fetal calf serum (FCS) in the static and dynamic modes. The morphology of alloy surfaces was analyzed using light microscopy and computed tomography. Biodegradation was assessed by calculating weight loss within a certain incubation period. Cell adhesion and colonization stimulation were quantified in terms of a cell index (CI) using an analyzer xCELLigence RTCA Systems (ACEA Biosciences, Inc., USA) during the incubation of HEK 293 cells on WE43 specimens. RESULTS: Strengthening of magnesium alloys Mg-Zn-Ca and WE43 using ECAP and, consequently, the changed structure resulted in the biodegradation acceleration as high as eightfold. Among the specimens incubated in FCS in different modes, those incubated in liquid flow exhibited the biodegradation rate twice as high as that of the specimens tested under static conditions. The biodegradation process was accompanied by local corrosion, although the degradation was primarily concentrated along the specimen margins stimulating cell adhesion and colonization. Such nature of degradation, as a rule, does not lead to anisotropy of the strength characteristics, that is important for medical materials. Superficial degradation of the alloys with no X-ray density changes in the bulk of the specimens was confirmed by computed tomography. CONCLUSION: The study of the biodegradation rate and further characteristics of magnesium alloys Mg-Zn-Ca and WE43 showed that the materials in both structural conditions are suitable for implants and can be used in bone implants and surgical fasteners.

Cost-utility analysis for advanced breast cancer therapy in Germany: results of the fulvestrant sequencing model.

Therapy decisions in advanced breast cancer (ABC) increasingly require assessment not only of treatment efficacy but also of cost-effectiveness. To this end, we performed a cost-utility analysis by comparing treatment sequences including/omitting fulvestrant in a hypothetical population of hormone receptor-positive (HR+) postmenopausal women with ABC. The analysis was performed from the German health care perspective. Using a first-order sequential Markov model, expected costs and utilities were calculated over a time horizon of 10 years for cohorts of patients with HR+ ABC, previously treated for at least 5 years using adjuvant endocrine therapies. Utilities were primarily quantified in terms of quality adjusted life years (QALY). "Base-case" estimates of state transition rates, resource utilization, and other model parameters were derived from published evidence and expert assessment. The impacts of uncertainties in all key model parameters were evaluated by sensitivity analysis. Costs and benefits were discounted at 3% annually. Including second-line fulvestrant in the treatment sequence led to greater estimated health gains (0.021 QALY) and cost savings of 564 euros ($745, 380 pounds) per patient, i.e. the fulvestrant-containing sequence was "dominant". The prediction of a cost savings was robust with respect to variations in all key parameters. The probability of acceptable cost-effectiveness for the fulvestrant sequence was 72% at a willingness to pay (WTP) of 30,000 euros/QALY ($39,621/QALY, 20,198 pounds/QALY); the probability was even higher at lower WTP and substantially exceeded 50% for any realistic WTP. In a representative population of women with HR+ advanced breast cancer, inclusion of fulvestrant in the treatment sequence provides a cost-effective alternative from the German health care perspective. A high probability of cost-effectiveness is maintained under variations in all key parameters. The results reflect a tendency for patients receiving fulvestrant at an early stage to maintain high quality of life for a longer interval.

The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor.

The membrane-anchored heparin-binding EGF-like growth factor precursor (proHB-EGF)/diphtheria toxin receptor (DTR) belongs to a class of transmembrane growth factors and physically associates with CD9/DRAP27 which is also a transmembrane protein. To evaluate the biological activities of proHB-EGF/DTR as a juxtacrine growth factor and the biological significance of its association with CD9/DRAP27, the mitogenic activity of proHB-EGF/DTR was analyzed using stable transfectants of mouse L cells expressing both human proHB-EGF/DTR and monkey CD9/DRAP27, or either one alone. Juxtacrine activity was assayed by measuring the ability of cells in co-culture to stimulate DNA synthesis in an EGF receptor ligand dependent cell line, EP170.7. LH-2 cells expressing human proHB-EGF/DTR stimulated EP170.7 cell growth moderately. However, LCH-1 cells, a stable co-transfectant expressing both human proHB-EGF/DTR and monkey CD9/DRAP27 cDNAs, dramatically unregulated the juxtacrine growth factor activity of proHB-EGF/DTR approximately 25 times over that of LH-2 cells even though both cell types expressed similar levels of proHB-EGF/DTR on the cell surface. Anti-CD9/DRAP27 antibodies which were not able to neutralize the mitogenic activity of soluble HB-EGF suppressed LCH-1 cell juxtacrine growth activity to the same extent as did anti-HB-EGF neutralizing antibodies and CRM 197, specific inhibitors of human HG-EGF. These findings suggest that optimal expression of the juxtacrine growth activity of proHB-EGF/DTR requires co-expression of CD9/DRAP27. These studies also indicate that growth factor potentiation effects which have been observed previously for soluble growth factors also occurs at the level of cell surface associated growth factors.

When are summary ROC curves appropriate for diagnostic meta-analyses?

Diagnostic tests are increasingly evaluated with systematic reviews and this has lead to the recent developments of statistical methods to analyse such data. The most commonly used method is the summary receiver operating characteristic (SROC) curve, which can be fitted with a non-linear bivariate random-effects model. This paper focuses on the practical problems of interpreting and presenting data from such analyses. First, many meta-analyses may be underpowered to obtain reliable estimates of the SROC parameters. Second, the SROC model may be inappropriate. In these situations, a summary with two univariate meta-analyses of the true and false positive rates (TPRs and FPRs) may be more appropriate. We characterize the type of problems that can occur in fitting these models and present an algorithm to guide the analyst of such studies, with illustrations from analyses of published data. A set of R functions, freely available to perform these analyses, can be downloaded from (www.diagmeta.info).

Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder.

The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified. Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth. This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo. ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder. These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury. Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder. Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.

Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.

BACKGROUND: The treatment of rest pain, ulceration, and gangrene of the leg (severe limb ischaemia) remains controversial. We instigated the BASIL trial to compare the outcome of bypass surgery and balloon angioplasty in such patients. METHODS: We randomly assigned 452 patients, who presented to 27 UK hospitals with severe limb ischaemia due to infra-inguinal disease, to receive a surgery-first (n=228) or an angioplasty-first (n=224) strategy. The primary endpoint was amputation (of trial leg) free survival. Analysis was by intention to treat. The BASIL trial is registered with the National Research Register (NRR) and as an International Standard Randomised Controlled Trial, number ISRCTN45398889. FINDINGS: The trial ran for 5.5 years, and follow-up finished when patients reached an endpoint (amputation of trial leg above the ankle or death). Seven individuals were lost to follow-up after randomisation (three assigned angioplasty, two surgery); of these, three were lost (one angioplasty, two surgery) during the first year of follow-up. 195 (86%) of 228 patients assigned to bypass surgery and 216 (96%) of 224 to balloon angioplasty underwent an attempt at their allocated intervention at a median (IQR) of 6 (3-16) and 6 (2-20) days after randomisation, respectively. At the end of follow-up, 248 (55%) patients were alive without amputation (of trial leg), 38 (8%) alive with amputation, 36 (8%) dead after amputation, and 130 (29%) dead without amputation. After 6 months, the two strategies did not differ significantly in amputation-free survival (48 vs 60 patients; unadjusted hazard ratio 1.07, 95% CI 0.72-1.6; adjusted hazard ratio 0.73, 0.49-1.07). We saw no difference in health-related quality of life between the two strategies, but for the first year the hospital costs associated with a surgery-first strategy were about one third higher than those with an angioplasty-first strategy. INTERPRETATION: In patients presenting with severe limb ischaemia due to infra-inguinal disease and who are suitable for surgery and angioplasty, a bypass-surgery-first and a balloon-angioplasty-first strategy are associated with broadly similar outcomes in terms of amputation-free survival, and in the short-term, surgery is more expensive than angioplasty.

Heparin-binding EGF-like growth factor.

HB-EGF is a heparin-binding member of the EGF family that was initially identified in the conditioned medium of human macrophages. Soluble mature HB-EGF is proteolytically processed from a larger membrane-anchored precursor and is a potent mitogen and chemotactic factor for fibroblasts, smooth muscle cells but not endothelial cells. HB-EGF activates two EGF receptor subtypes, HER1 and HER4 and binds to cell surface HSPG. The transmembrane form of HB-EGF is a juxtacrine growth and adhesion factor and is uniquely the receptor for diphtheria toxin. HB-EGF gene expression is highly regulated, for example by cytokines, growth factors, and transcription factors such as MyoD. HB-EGF has been implicated as a participant in a variety of normal physiological processes such as blastocyst implantation and wound healing, and in pathological processes such as tumor growth, SMC hyperplasia and atherosclerosis.

Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study.

PURPOSE: To investigate the effect of adding tamoxifen to a preoperative dose-dense doxorubicin and docetaxel regimen on the pathologic response of primary operable breast cancer. PATIENTS AND METHODS: Patients (tumor size > or = 3 cm, N0 to 2, M0) were prospectively randomized to receive every 14 days a total of four cycles of doxorubicin 50 mg/m2 and docetaxel 75 mg/m(2), either with (ADocT) or without (ADoc) simultaneous tamoxifen. Granulocyte colony-stimulating factor (G-CSF) was routinely given on days 5 to 10. Surgery followed 8 to 10 weeks after the start of treatment. RESULTS: Within 14 months, 250 patients were included in the study at 56 centers. Of 992 planned cycles, 97.9% were administered. Pathologically complete remission (pCR) with no detectable viable tumor cells was achieved in 9.7%. There was a nonsignificant difference of -1.2% in favor of ADoc, with a 95% confidence interval of -8.6% to 6.2%. A further 2.4% had only noninvasive tumor residues, and 13.8% had focal invasive residues. Complete and partial responses detected by palpation were observed in 28.9% and 52.4%, respectively. The response rates (complete and partial) by best appropriate imaging methods were 77.5% and 67.5% for ADocT and ADoc, respectively. Breast conservation was possible in 68.8% of the patients. A tendency toward more frequent toxic events was observed with ADocT treatment. Significant predictors of pCR to chemotherapy were negative lymph node and negative estrogen receptor status. CONCLUSION: A dose-dense regimen of ADoc with G-CSF offers high compliance, moderate toxicity, and rapid efficacy as a form of preoperative chemotherapy in operable breast cancer. Concurrent treatment with tamoxifen for 8 weeks could not improve the pathologic response rate.

HIV infection in women: immunological markers and the influence of pregnancy.

OBJECTIVE: To describe the influence of pregnancy on immunological marker paths and progression of HIV-infected women. DESIGN: Analysis of prospectively collected immunological and clinical data collected on 145 women reviewed at the City Hospital, Edinburgh, between 1985 and 1992 using a two-level random-effects model that allows for within- and between-patient variance. RESULTS: There were differences between the marker paths of women according to risk activity; women who had acquired HIV via injecting drug use (in addition to heterosexual intercourse) had a higher level of absolute CD4 cells, CD4% and total lymphocytes at seroconversion than those who had acquired HIV via heterosexual intercourse alone; however, immunological markers declined more steeply after seroconversion. There was no evidence that pregnancy, either before or after HIV seroconversion had an adverse effect on marker paths of HIV disease. There was a significant association between pregnancy after HIV seroconversion and post-pregnancy changes in immunological markers: an increase in the CD4% and a decrease in CD8%. However, causality cannot be implied as pregnancy itself may be associated with considerable lifestyle changes. During pregnancy the total white blood count rose due to an increase in the number of granulocytes, whereas the total lymphocyte numbers fell. The absolute CD4 lymphocyte subset counts fell progressively but the effect was due to the fall in the total lymphocyte counts, there being no influence of pregnancy on either CD4% or CD8%. CONCLUSIONS: In asymptomatic HIV infection, changes in the absolute levels of CD4 and CD8 lymphocyte counts are primarily related to changes in the other components of the white cell count because there were no changes in CD4% and CD8%. Pregnancy itself has no adverse effect on immunological markers of HIV.

HIV prevalence and risk factors in university students.

OBJECTIVE: To estimate HIV prevalence and risks in university students. DESIGN: Anonymous self-completion questionnaire and HIV survey with saliva samples. SETTING: University students at matriculation. PARTICIPANTS: All first and third year undergraduates and newly registering postgraduates at the University of Edinburgh, Scotland. MAIN OUTCOME MEASURES: HIV prevalence, sexual behaviour, condom use, drug use. RESULTS: The questionnaire responses were used to classify the 4665 respondents into four groups, ordered by risk of HIV positivity, and a sample of 2041 was selected for testing. All of the top two risk groups were tested (217 and 758 tests, respectively) as well as a random sample of the others. Five positive HIV-antibody tests were detected, all from the highest risk group. This gives an estimated rate of 1.2 per 1000 (95% confidence interval, 0.4-2.9) for all respondents. Only one of the five HIV-positives had been tested for HIV. The factors associated with HIV positivity were residence in Africa, intravenous drug use and male homosexuality. Overall, 74% of respondents reported ever having had sexual intercourse and this rate was the same for men and women. Reported intravenous drug use was very low: 0.5% for men and 0.1% for women. Condom use was more common for partners of short acquaintance, but unrelated to the number of sexual partners in the last year. CONCLUSIONS: There was no evidence of the spread of HIV infection beyond known high-risk groups in this population. This may be a result of relatively low levels of HIV risk-taking behaviour in the majority of respondents.

PIP: In Scotland during 1993-1994, 4665 first and third year undergraduates, newly registering postgraduates, and nongraduating students at the University of Edinburgh completed a questionnaire. Based on responses, the researchers categorized the students into four risk groups. One group consisted of men with male sex partners in the last year, permanent home in Africa, IV non-medically prescribed drug use, ever shared needles or works, ever paid or been paid money for sex, professionally exposed to blood. The second group include those not in the first group but had more than 3 sex partners in the last year, or persons with more than 2 sex partners in the last year and no condom use at last intercourse, or sexual intercourse with a resident of Africa. Persons who were neither in the first two groups nor the fourth group comprised the third group. Persons who never had sex and were not in group one comprised group four. They submitted saliva tests to all students in the top two risk groups and to a random sample of those in the other groups for a total of 2041 students. The researchers aimed to determine HIV prevalence and risk factors. All five HIV seropositive students were from the highest risk group for an overall HIV prevalence rate of 1.2/1000. The HIV prevalence rate for those just in the highest risk group was 22/1000. Only one of these HIV seropositive students had been tested earlier for HIV. HIV infections were limited to persons with a permanent home in Africa, IV drug use, and male homosexual intercourse. All but one HIV seropositive individual were males. 73.7% of all respondents had ever engaged in sexual intercourse. IV drug use was rare (0.5% for men and 0.1% for women). 52% of respondents used a condom during last intercourse. Condom use was associated with short acquaintance of partners. The number of sexual partners in the last year did not affect condom use. These findings indicate that HIV transmission appears to be confined to high risk groups, probably because most students did not practice risky behavior.

Cytochrome P450 mediated reactions studied in genetically engineered V79 Chinese hamster cells.

V79 Chinese hamster cells genetically engineered for stable expression of rat and human CYP have been shown to serve as analytical tools for studying metabolism related problems in toxicology and pharmacology. Here, the application of rat and human CYP1A1 and CYP1A2 is demonstrated for comparative studies on the oxidation of polycyclic aromatic hydrocarbons, such as phenanthrene, benz[a]anthracene, and benzo[a]pyrene. Live cells were cultivated for 2 days in the presence of these chemicals. Thereafter, the supernatant medium was checked for metabolites by gas chromatography and mass spectrometry. Marked cytochromes P450 and species dependent differences in the metabolite profiles were observed. Most important was the finding, that human cytochrome P450 1A1 almost exclusively oxidized benzo[a]pyrene in the 7,8,9,10-position, yielding the ultimate carcinogen 7,8-dihydroxy-9,10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrene whereas the rat cytochrome P450 1A1 oxidized benzo[]pyrene in the 4,5-position and 7,8,9,10-position. The importance of this finding is underlined by results from cytotoxicity studies. Benzo[a]pyrene was twice as cytotoxic in the human cytochrome P450 1A1 than in the rat cytochrome P450 1A1 expressing V79 cells. Species and cytochrome P450 specific metabolite profiles were also observed for phenanthrene and benz[a]anthracene.

The role of docetaxel (Taxotere) in neoadjuvant chemotherapy of breast cancer.

Neoadjuvant chemotherapy has become standard therapy in the management of breast cancer patients with locally advanced disease with inoperable tumors and inflammatory breast cancer. Patients with earlier stage breast cancer and operable tumors may also benefit from treatment with neoadjuvant chemotherapy. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) is thought to be one of the most potent agents in the treatment of metastatic breast cancer and is therefore being investigated for its likely benefit in preoperative, neoadjuvant regimens. Several large phase II and randomized phase III trials are evaluating docetaxel as a single agent, in combination, and/or sequentially in the preoperative setting. Preliminary findings demonstrate high complete and partial response rates and a tolerable toxicity profile. These results are consistent with the view that incorporation of docetaxel in neoadjuvant chemotherapy regimens will contribute to improved patient outcome. Ongoing studies will provide important information regarding the most appropriate regimens and schedules of docetaxel to use in the preoperative, neoadjuvant setting.

Standardisation and quality assurance of lymphocyte proliferation assays for use in the assessment of immune function. European Concerted Action on Immunological and Virological Markers of HIV Disease Progression.

Lymphocyte proliferation is a widely used technique to assess immune competence. However, the technique is subject to a large degree of variation, some biological and some technical. In this study, the components of variation in whole blood proliferation assays were analysed over time, using both antibody and mitogenic stimulants. The levels of variation within individual samples, between individuals and between groups of individuals over time were examined. A method of transforming the data is proposed which reduces the coefficients of variation to an acceptable level, and which expresses individual results as a standardised count. This method overcomes the problem of different levels of absolute counts, it corrects for time sensitive errors and allows data from multiple laboratories to be pooled.

Monooxygenase induction by various xenobiotics and its influence on rat liver microsomal metabolism of chrysene in comparison to benz[a]anthracene.

The potencies of various xenobiotics for induction of monooxygenases and their influence on the rat liver microsomal metabolite profile of the environmentally relevant weak carcinogen, chrysene, was determined. Among the widely distributed chemicals, polychlorinated biphenyls (PCB) and preferentially 3,3',4,4'-tetrachlorobiphenyl as well as PAHs and their heterocyclic analogues such as benzo[a]pyrene, benzo[b]- and -[j]fluoranthene, indeno[1,2,3-cd]pyrene, dibenz[a,h]acridine, benzo[b]naphtho-[2,1-d]thiophene, and 5,6-benzoflavone were found to be potent inducers stimulating the formation of the proximate, and some of them also the ultimate carcinogen of chrysene. Lindane, carbaryl, DDT, and pentachlorophenol were found to be inefficient or weak inducers. With the exception of phenobarbital no inducers were found among the pharmaceuticals investigated. Sex-dependent metabolism was found for Wistar-rats. No 1,2-oxidation was observed in females, and turnover rates were lower than in males. These findings confirm the results previously obtained with benz[a]anthracene as substrate. The inducing potencies of various compounds tested were similar for both of these substrates. It is interesting to note that in most cases the same effective xenobiotic induces the bay-region diolepoxide in both, chrysene and benz[a]anthracene.

Induction of specific monooxygenases by isosteric heterocyclic compounds of benz[a]anthracene, benzo[c]phenanthrene and chrysene.

Benzo[c]phenanthrene and a series of heterocyclic compounds (benzo[b]naphtho(1,2-d)thiophene; benzo[b]naphtho(2,1-d)thiophene; benz[a]acridine and benz[c]acridine) were tested to their capacity of inducing monooxygenase activity in rat liver by means of recording the metabolite profile of benz[a]anthracene formed in rat liver microsomal incubations. Although all compounds tested were found to be weak monooxygenase inducers the pretreatment of rats with them resulted in significant changes of the microsomal metabolite profile of benz[a]anthracene. The thiophenes equally gave rise to oxidation at the 5,6- and the 8,9-positions, whereas the benzacridines being isosteric to benz[a]anthracene favoured the K-region oxidation (5,6-oxidation). A structure-dependent effect of monooxygenase inducers on the metabolite profile of benz[a]anthracene is discussed.

On the metabolic activation of benz[a]acridine and benz[c]acridine by rat liver and lung microsomes.

The metabolism of benz[a]- and benz[c]acridine by liver and lung microsomes from untreated, phenobarbital (PB)-treated and benzo[k]fluoranthene (BkF)-treated rats has been studied by gas chromatography/mass spectrometry (GC/MS). Epoxidation and hydrolysis of the epoxides to dihydrodiols were found to be the predominant pathways for all substrates. N-Oxidation is likely to occur in the case of benz[c]acridine. However, no unequivocal evidence could be obtained for the formation of the ultimate carcinogens--the t-3,4-dihydrodiol-1,2-epoxides--in case of both benz[a]- and benz[c]acridine. K-Region oxidation was induced by phenobarbital, whereas the formation of non-K-region metabolites increased after BkF treatment in the case of benz[c]acridine.

Monooxygenase induction by various xenobiotics and its influence on the rat liver microsomal metabolite profile of benz[a]anthracene.

Several pesticides (lindane, carbaryl, pentachlorophenol, DDT), polycyclic aromatic hydrocarbons (PAH) and heterocyclic analogues (fluoranthene, dibenz[a,h]anthracene, dibenz[a,h]acridine, indeno[1,2,3-cd]pyrene, 10-azabenzo[a]pyrene) and pharmaceuticals (diphenylhydantoin, ethinylestradiol, levonorgestrel) were tested for their potencies to induce monooxygenase activities in the rat liver by means of recording the metabolite profile of benz[a]anthracene in rat liver microsomal incubations. Some of them were found to be weak or moderate inducers, but even less efficient ones altered the benz[a]anthracene metabolite profile significantly. Only indeno [1,2,3-cd]pyrene stimulated the bay-region oxidation of benz[a]anthracene. A sex-dependent metabolism was observed in both untreated and contraceptive-pretreated Wistar rats.

Comparison of chrysene metabolism in epithelial human bronchial and Syrian hamster lung cells.

Chrysene is metabolized to 1-, 2-, 3-, and 4-hydroxychrysene and trans-1,2- as well as trans-3,4-dihydroxydihydrochrysene in human and Syrian hamster epithelial lung cells as indicated by GC/MS analysis, whereas K-region oxidation is at most a very minor pathway. Cells of a permanent clonal line of fetal hamster lung metabolized 97% of the chrysene whereas fetal human bronchial epithelial cells converted 24% of the substrate within 8 days incubation. In human cells oxidation at the 3,4-position predominates, whereas oxidation at the 1,2-position is the major pathway in hamster cells. Indication for a bay-region oxidation of chrysene in hamster cells has been obtained.

The effect of human immunodeficiency virus infection and drug use on birth characteristics.

OBJECTIVE: To explore the effect of human immunodeficiency virus (HIV) infection and drug use on birth weight, length, and gestational duration at delivery. METHODS: Subjects had a history of injection drug use or a sexual partner who was an injection drug user, were Scottish, and their HIV serostatus during pregnancy was known. Control pregnancies were matched for age, parity, ethnic group, year of delivery, and postal code sector of home address. In addition, some were matched for smoking and housing deprivation score. Birth weights were standardized for gestational age by expressing them as z scores with a mean of zero and a standard deviation of unity. Statistical analysis was by univariate and multiple regression with multilevel modeling. RESULTS: Regression analysis for birth weight, gestational age, and gestation-adjusted birth weights (z score) included 789 pregnancies in 693 women. Human immunodeficiency virus seropositivity was associated with a z score that was 0.27 lower (P = .03), but there was no significant difference in gestational duration at delivery. Current oral or injection drug use were associated with a reduction in standardized birth weight (z score -0.27, P = .06, and z score -0.28, P = .04, respectively), and injection drug use with a reduction in occipitofrontal circumference only (1.8 cm reduction, P = .05). Injection drug use, but not the other factors, had an effect on gestational age at delivery (1.54 weeks earlier, P < .001). CONCLUSION: Although HIV seropositivity is associated with a small reduction in standardized birth weight, this effect is less than that attributable to smoking and may not be of clinical significance. The effect seems to be associated with placental size. Opiate use, regardless of route, had a small association with reduced birth weight, suggesting a specific drug effect. However, only injection drug use had a strong association with early delivery, and this effect was likely to be clinically significant at the population level.