'A band of brothers'-an exploration of the range of medical ethical issues faced by British senior military clinicians on deployment to Afghanistan: a qualitative study.

AIMS: To identify and explore features of ethical issues that senior clinicians faced as deployed medical directors (DMDs) to the British Field Hospital in Afghanistan as well as to determine the ethical training requirements for future deployments. METHOD: A qualitative study in two phases conducted from November 2014 to June 2015. Phase 1 analysed 60 vignettes of cases that had generated ethical dilemmas for DMDs. Phase 2 included focus groups and an interview with 13 DMDs. FINDINGS: Phase 1 identified working with limited resources, dual conflict of meeting both clinical and military obligations and consent of children as the most prevalent ethical challenges. Themes found in Phase 2 included sharing clinical responsibilities with clinicians from other countries and not knowing team members' ways of working, in addition to the themes from Phase 1. DISCUSSION: This study has drawn together examples of scenarios to form a repository that will aid future training. Recommendations included undertaking ethics training together as a team before, during and after deployment which must include all nationalities who are assigned to the same operational tour, so that different ethical views can be explored beforehand.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 µg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 µg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 µg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

Pharmacokinetics of isoniazid in low-birth-weight and premature infants.

Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 µg/ml, the time after drug administration to reach CmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2-5) was 13.56 µg · h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h(-1). The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children.

Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.

A qualitative study of the use of the four quadrant approach to assist ethical decision-making during deployment.

AIM: The aim of the study was to explore how useful clinicians deployed to the Field Hospital in Afghanistan found using the four quadrant approach (4QA) as a tool to aid ethical decision-making. In addition, the study aimed to determine whether the 4QA needed to be amended to make it more effective in assisting the ethical decision-making process for military health professionals on deployment. METHOD: A qualitative pilot study in two phases was undertaken between September 2012 and January 2013. In Phase I, senior deployed clinicians completed a pro forma of the 4QA on cases that potentially raised ethical issues. Thirteen pro formas were submitted on four cases; the Deployed Medical Director submitted a log of 14 cases that had involved using the 4QA. Phase II consisted of interviews with five senior clinicians who had recently returned from deployment in Afghanistan to discuss their experiences and perceptions of using the 4QA. RESULTS: Phase I identified a variation in the level of detail recorded and where that information was placed on the quadrant. Four themes were generated from Phase II. These included the characteristics of ethical decisions; the processes used to make ethical decisions; use, usefulness and limitations of the 4QA; and views about training in ethics. The findings suggested that amendments to the pro forma may improve its utility. CONCLUSIONS: The 4QA is a useful tool within an operational setting but amending its diagrammatic presentation could improve its effectiveness. Pre-deployment training should include practising using the quadrant as described in Clinical Guidelines for Operations. This is particularly important as the participants relied heavily on experience to help them make ethical decisions, and this experience may not be available in future operations outside Afghanistan.

Acceptability of levofloxacin dispersible and non-dispersible tablet formulations in children receiving TB preventive treatment.

BACKGROUND: We evaluated the palatability and acceptability of a 100 mg dispersible and a non-dispersible 250 mg levofloxacin (LVX) tablet formulation in children. METHODS: Perform was a randomised, open-label, cross-over trial of the relative bioavailability of LVX dispersible vs. crushed non-dispersible tablets in children aged <6 years routinely receiving TB preventive treatment. Children and caregivers completed Likert- and ranking-type measures on the acceptability of both formulations. We used summary, comparative and ranking statistics to characterise formulation acceptability. RESULTS: A total of 25 children were enrolled (median age: 2.6 years, IQR 1.6-4.0). Caregivers reported frequent challenges with preventive therapy in routine care prior to study entry, including taste of tablets (n = 14, 56%), vomiting/spitting out medicines (n = 11, 44%), and children refusing medicines (n = 10, 40%). Caregivers reported that the dispersible formulation was easier for their child to take than the non-dispersible formulation (P = 0.0253). Mean ranks for caregiver's formulation preferences (dispersible tablets: 1.48, SD ±0.71; non-dispersible tablets: 2.12, SD ±0.67; routinely available formulations: 2.40 SD ±0.82) differed significantly (Friedman's F 11.120; P < 0.0038); post-hoc testing showed dispersible tablets were preferred over non-dispersible (P = 0.018) and routinely available LVX formulations (P < 0.001). CONCLUSIONS: The dispersible LVX 100 mg tablet formulation was preferred and should be prioritised for integration into routine care.

CONTEXTE: Nous avons évalué la palatabilité et l'acceptabilité d'un comprimé dispersible de 100 mg et d'un comprimé non dispersible de 250 mg de lévofloxacine (LVX) chez les enfants. MÉTHODES: Perform était un essai randomisé, ouvert et croisé de la biodisponibilité relative des comprimés dispersibles LVX par rapport aux comprimés non dispersibles écrasés chez des enfants âgés de moins de 6 ans recevant régulièrement un traitement préventif contre la TB. Les enfants et les soignants ont rempli des questionnaires de type Likert et de classement sur la tolérance des deux formulations. Nous avons utilisé des statistiques sommaires, comparatives et de classement pour caractériser la tolérance à la formulation. RÉSULTATS: Au total, 25 enfants ont été recrutés (âge médian : 2,6 ans ; IQR 1,6­4,0). Les soignants ont signalé des problèmes fréquents liés au traitement préventif dans le cadre des soins de routine avant le début de l'étude, notamment le goût des comprimés (n = 14, 56%), le fait de vomir ou de recracher les médicaments (n = 11, 44%) et le fait que les enfants refusent les médicaments (n = 10, 40%). Les soignants ont déclaré que la formulation dispersible était plus facile à prendre pour leur enfant que la formulation non dispersible (P = 0,0253). Les classements moyens pour les préférences de formulation des soignants (comprimés dispersibles : 1,48 ; SD ±0,71 ; comprimés non dispersibles : 2,12 ; SD ±0,67 ; formulations couramment disponibles : 2,40 ; SD ±0,82) différaient de manière significative (Friedman's F 11,120 ; P < 0,0038) ; les tests post-hoc ont montré que les comprimés dispersibles étaient préférés aux comprimés non dispersibles (P = 0,018) et aux formulations LVX couramment disponibles (P < 0,001). CONCLUSION: La formulation dispersible des comprimés de LVX 100 mg a été préférée et devrait être intégrée en priorité dans les soins de routine.

Treatment outcomes and safety in children with rifampicin-resistant TB.

BACKGROUND: The treatment of rifampicin-resistant TB (RR-TB) in children is evolving rapidly. As newer regimens are introduced into routine care, it is vital to compare their outcome and safety with well-characterised clinical cohorts treated with historical regimens.METHODS: Study sample comprised a prospective observational cohort of children on routine RR-TB treatment, enrolled from 2011 to 2015 in Cape Town, South Africa. Children were followed for safety, treatment response and outcome.RESULTS: Of 136 children included, 27 (19.9%) were living with HIV and 48 (37.8%) had severe TB. The median time-to-culture conversion in children with bacteriological confirmation (n = 44) was 28.5 days (IQR 14.5-45). Overall, 118/129 (91.5%) had favourable TB treatment outcomes. Of 106 (77.9%) children who received an injectable drug, 9 (8.5%) developed hearing loss and 7/136 (5.1%) developed other Grade 3 or higher adverse events likely related to treatment.CONCLUSIONS: In this cohort with a substantial proportion of children with severe manifestations of TB and with HIV, TB treatment outcomes were excellent. Apart from hearing loss, few children developed severe adverse events related to treatment. This study provides robust reference data for future evaluation of shorter, injectable-sparing regimens.

The effect of seeking consent on the representativeness of patient cohorts: iron-deficiency anaemia and colorectal cancer.

AIM: The study aimed to establish the level of selection bias that may occur should individual patient consent be sought, by comparing characteristics of consenters and nonconsenters to a request for access to medical records within a cohort of patients diagnosed with iron-deficiency anaemia (IDA). METHOD: A cohort study and cross-sectional survey was carried out of consent preferences that compared the sociodemographic characteristics of patients providing or not providing consent for access to their records, the consent rates by participant subgroup and the predictors of consent/nonconsent. RESULTS: Of 599 patients mailed requesting consent for access to their medical records, 425 (71.0%) responses were received. Of the valid responses, explicit consent was granted by 371 (62.7%) respondents, with 47 (7.9%) refusals. The characteristics of consenters and nonconsenters differed with regard to age, gender and deprivation quartile. Nonconsent was associated with younger age (40-60 years vs 60 + years; bivariate OR = 2.84; 95% CI = 2.01-4.02), female gender (OR = 1.62; 95% CI = 1.13-2.34) and being socioeconomically deprived (OR = 1.61; 95% CI = 1.15-2.26). CONCLUSION: The current research governance framework demonstrates a conflict between protecting the rights of the individual and the development of a sound research base to improve the delivery of healthcare services for society as a whole. If epidemiological research includes data only from individuals who have given consent for access to their records, the resulting selection bias may have consequences for the scientific validity and generalizability of research findings, and ultimately the quality of patient care.

Pharmacokinetics of high-dose isoniazid in children affected by multidrug-resistant TB.

BACKGROUND: High-dose isoniazid (INHH) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse.METHODS: This observational study included South African children (<15 years) receiving INHH as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC0-24) and maximum concentration (Cmax). AUC and Cmax values were compared against proposed adult targets.RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC0-24 was 19.46 µgh/mL (IQR 10.76-50.06) and Cmax was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC0-24 (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; P < 0.001) and Cmax (GMR 0.20, 95% CI 0.15-0.26; P < 0.001).CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

Healthcare workers' perceptions of the duty to work during an influenza pandemic.

Healthcare workers (HCWs) are often assumed to have a duty to work, even if faced with personal risk. This is particularly so for professionals (doctors and nurses). However, the health service also depends on non-professionals, such as porters, cooks and cleaners. The duty to work is currently under scrutiny because of the ongoing challenge of responding to pandemic influenza, where an effective response depends on most uninfected HCWs continuing to work, despite personal risk. This paper reports findings of a survey of HCWs (n = 1032) conducted across three National Health Service trusts in the West Midlands, UK, to establish whether HCWs' likelihood of working during a pandemic is associated with views about the duty to work. The sense that HCWs felt that they had a duty to work despite personal risk emerged strongly regardless of professional status. Besides a strong sense that everyone should pull together, all kinds of HCWs recognised a duty to work even in difficult circumstances, which correlated strongly with their stated likelihood of working. This suggests that HCWs' decisions about whether or not they are prepared to work during a pandemic are closely linked to their sense of duty. However, respondents' sense of the duty to work may conflict with their sense of duty to family, as well as other factors such as a perceived lack of reciprocity from their employers. Interestingly, nearly 25% of doctors did not consider that they had a duty to work where doing so would pose risks to themselves or their families.

A double-blinded randomised controlled study to investigate the effect of intraperitoneal levobupivacaine on post laparoscopic pain.

BACKGROUND: Laparoscopic surgery is the cornerstone of modern gynaecological surgery, with shorter hospital stays and a quicker return to normal activities. However postoperative pain remains problematic. No strategy to reduce phrenic nerve irritation, including heating or humidifying the insufflating gas, alternatives to CO2, and intraperitoneal analgesics, has shown superiority. METHODS: 100 women undergoing laparoscopic surgery were randomly allocated, having either 40ml of 0.25% levobupivacaine or 40ml 0.9% sodium chloride solution administered into the peritoneal cavity following surgery. The patients and the main researcher were blinded. All women received standardised anaesthetic and laparoscopic technique, and postoperative pain control including nursing position and nature of analgesia. Postoperative pain was assessed 3 hours, 8 hours, day 1 and day 4/5 postoperatively. RESULTS: 100 patients were recruited undergoing surgery for benign causes aged 19-73(mean 40.3±13). There was no difference between the groups for age(p=0.64) or length of operation(p=0.56). There were no adverse events related to use of intraperitoneal instillation. There was a significant reduction in shoulder-tip pain scores in the levobupivacaine group at 3 hours(p=0.04). Furthermore, there was a significant reduction in wound-pain scores in the levobupivacaine group at 8hrs(p=0.04) and at day 4(p=0.04). No difference was found in pelvic pain between the two groups. No significant difference was found in the use of post-operative analgesia. CONCLUSIONS: Intraperitoneal instillation of 40ml of levobupivacaine has some benefit in reducing postoperative pain and need for analgesia in the initial hours following gynaecological surgery. However, further well-designed randomised control trials are required to decide the optimum route and concentration of administering local anaesthetic.

Medical education and patients' responsibilities: back to the future?

Medical student learning is dependent on an unwritten agreement between patients and the medical profession, in which students "practise" upon real patients in order that, when they are doctors, those same patients will benefit from the doctors' skills. Given the increasing propensity for patients to refuse to take part in such learning, there is a danger that doctors will qualify without being truly competent. As patients, we must all ask ourselves, when asked to take part in medical teaching: if this student/trainee doesn't learn now, on me and under supervision, how will the person be truly competent next time, when this is for real, and the patient might be me or my loved one? We argue that a new and more explicit agreement is needed, in which the default should be that all patients are willing to help in the education of medical students, while we ensure that all such students are already competent in simulation before first practising upon real patients.

Medical students' attitudes towards abortion: a UK study.

BACKGROUND: There is little research into medical students' or doctors' attitudes to abortion, yet knowing this is important, as policy makers should be aware of the views held by professionals directly involved in abortion provision and changing views may have practical implications for the provision of abortion in the future. METHODS: We surveyed 300 medical students about their views on abortion, their beliefs about the status of the fetus and the rights of the mother, their attitude towards UK law and their willingness to be involved in abortion provision as qualified doctors. RESULTS: 62% of medical students were pro-choice, 33% pro-life and 7% undecided. Students' views correlated with gender, year of study and holding a religious belief. Their beliefs about abortion, the status of the fetus and the rights of women significantly correlated with their attitudes towards the UK law and their willingness to be involved in abortion provision. Students' willingness to be involved in abortion provision was related to their views on abortion, the extent of participation required, the circumstances of the pregnancy and the stage of pregnancy. CONCLUSIONS: The percentage of pro-choice students was lower than that found in research on general practitioners' attitudes to abortion. It is unclear whether this is because students become more pro-choice as they progress through their medical career or because there is genuinely a change in attitudes to abortion.

What drives 'first-time testers' to test for HIV at community-based HIV testing services?

Drivers of and barriers to testing are not well understood for those who have never been tested previously and now self-initiate at a community-based human immuno-deficiency virus (HIV) testing service (CB-HTS). This descriptive study enrolled 229 first-time testers. Participants completed an electronic questionnaire. The majority reported fear and (non) accessibility of HTS as barriers to testing (40% and 24%, respectively). Wanting 'to know my status' and the immediate opportunity to test were reported as drivers of testing (41% and 35%, respectively). Addressing fear of testing and providing an easily accessible opportunity to test may go some way to encouraging those previously untested individuals to test.

Les facteurs qui amènent à réaliser un test et ceux qui les entravent ne sont pas bien compris pour ceux qui n'ont jamais été testés auparavant et en prennent l'initiative dans un service de test pour le virus de l'immunodéficience humaine (VIH) basé en communauté (CB-HTS). Cette étude descriptive a enrôlé 229 patients testés pour la première fois. Les participants ont rempli un questionnaire électronique. La majorité a déclaré que la crainte et la (non) accessibilité du HTS étaient des entraves au test (40% et 24%, respectivement). Vouloir « connaître son statut ¼ et l'opportunité de faire le test immédiatement ont été les moteurs de la réalisation du test (41% et 35%, respectivement). Répondre aux craintes individuelles de se faire tester et offrir une opportunité facilement accessible de le réaliser contribueraient à amener au test ceux qui ne l'ont jamais fait.

No se conocen plenamente los impulsores y los obstáculos a la práctica de las pruebas diagnósticas de la infección por el virus de la inmunodeficiencia humana (VIH), en las personas que nunca han recibido la prueba y que ahora, por iniciativa propia, acuden a los servicios comunitarios que la ofrecen. En el presente estudio descriptivo se incorporaron 229 personas que recibían la prueba diagnóstica por primera vez. Los participantes completaron un cuestionario en formato electrónico. La mayoría refirió como obstáculos a la práctica de la prueba el temor (40%) y la (falta de) accesibilidad de los servicios que la ofrecen (24%). Los factores referidos como impulsores de la búsqueda de la prueba fueron el hecho de 'querer conocer su estado' (41%) y la oportunidad inmediata de hacerla (35%). Abordar el temor de las personas y ofrecer una oportunidad fácilmente accesible de realizar la prueba diagnóstica del VIH puede contribuir a que las personas que nunca han realizado la prueba, la acepten.

Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children.

SETTING: Isoniazid-resistant rifampicin-susceptible (HRRS) tuberculosis (TB) is the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes, but has been poorly described in children. OBJECTIVE: To characterise the clinical presentation, treatment, and clinical and microbiological outcomes among children with culture-confirmed HRRS TB. DESIGN: Retrospective hospital-based cohort study. RESULTS: Of the 72 children included in the study, the median age was 50.1 months (IQR 21.5-102.5); 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed HRRS TB. Of 66 tested, 12 (17%) were human immunodeficiency virus (HIV) infected, and 36 (60%) of the 60 with pulmonary TB (PTB) had severe disease. Seventy children had treatment data; the median total duration of treatment was 11.3 months (IQR 9-12.3); 25 (36%) initiated treatment with a three-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 children with known outcomes, 55 (88%) had a favourable outcome, 1 died and 3 had treatment failure. Ten had positive follow-up cultures at ⩾2 months after starting treatment. Older age (P = 0.008), previous anti-tuberculosis treatment (P = 0.023) and severe PTB (P = 0.018) were associated with failure to culture-convert at ⩾2 months. CONCLUSIONS: Although overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasise the need for additional attention to the management of children with HRRS TB.

Isolation of a malondialdehyde-deoxyguanosine adduct from rat liver DNA.

In previous studies, an adduct of malondialdehyde (MDA) with guanine was identified in rat and human urine. Subsequent detection of an adduct with deoxyguanosine (dG) in urine prompted an investigation of its possible occurrence in DNA. Rat liver DNA was hydrolyzed using nuclease P1 and alkaline P-ase and subjected to deoxyribonucleoside analysis using reverse phase high-pressure liquid chromatography (HPLC) with fluorescence detection. A compound was isolated that could not be separated from a synthetic pyrimidinopurine adduct of MDA and dG (dG-MDA). Partial hydrolysis released guanine (Gua), Gua-MDA, and dG in amounts that, in aggregate, were the molar equivalent of the starting material calculated by fluorescence analysis as dG-MDA. Complete acid hydrolysis of the isolate yielded an equimolar amount of MDA. Analysis of liver DNA isolated from growing rats yielded a value for dG-MDA content of 9.0 +/- 1.6 pmol/100 micrograms DNA (mean +/- SEM, N = 5). This value is approximately 7 times those reported for the 8-hydroxy deoxyguanosine content of rat liver nuclear DNA. This study demonstrates that DNA is modified in vivo by reactions of its guanylate moiety with MDA, and indicates that, at least in the case of rat liver DNA, the prevalence of such modifications is greater than those caused by reactions with hydroxyl radicals.

Micronutrients and cancer prevention: are the RDAs adequate?

The involvement of certain micronutrients (vitamin C, vitamin E, beta-carotene, selenium) in the antioxidant defense system against free radical cell damage, and of vitamin A in the differentiation of epithelial cells, has raised the question whether intakes of these nutrients in excess of their recommended daily allowances should be recommended to the general public for cancer prevention. The considerations surrounding this question are discussed, and it is concluded that such measures are unjustified by present epidemiological and experimental evidence. Any such action should await the outcome of ongoing intervention trials.

Identification of N-(2-propenal)ethanolamine as a urinary metabolite of malondialdehyde.

N-(2-propenal)ethanolamine was isolated from rat and human urine using anion exchange, cation exchange, size exclusion and high performance liquid chromatography. Acid hydrolysis of the isolate yielded malondialdehyde (MDA) and ethanolamine (E) in a 1:1 molar ratio. A 1:1 E-MDA adduct was synthesized and found to be chromatographically inseparable from the urinary metabolite. Its NMR and UV spectra and lack of fluorescence were consistent with those of an enaminal formed by a Schiff's base reaction. The identification in urine of an adduct of MDA with ethanolamine, and the previous identification of an adduct with serine, constitutes direct evidence for the oxidative decomposition in vivo of polyunsaturated fatty acids present in the relevant phospholipids. The absence in urine of MDA adducts with other alpha-amino compounds (at least in comparable amounts) indicates that the ethanolamine and serine derivatives are formed in situ and not as a result of reactions with MDA generated in enzymatic processes.

Urinary aldehydes as indicators of lipid peroxidation in vivo.

The excretion of malondialdehyde (MDA), lipophilic aldehydes and related carbonyl compounds in rat and human urine was investigated. MDA was found to be excreted mainly in the form of two adducts with lysine, indicating that its predominant reaction in vivo is with the lysine residues of proteins. Adducts with the phospholipid bases serine and ethanolamine and the nucleic acid bases guanine and deoxyguanosine also were found. Except for the adduct with deoxyguanosine (dG-MDA), the excretion of these compounds increased with peroxidative stress imposed in the form of vitamin E deficiency or the administration of iron or carbon tetrachloride. Marked differences in the concentration of dG-MDA in different tissues were correlated with their content of fatty acids having three or more double bonds, the putative source of MDA. Fourteen nonpolar and eleven polar lipophilic aldehydes and other carbonyl compounds were identified as their 2,4-diphenylhydrazine derivatives in rat urine. The excretion of five nonpolar and nine polar compounds was increased under conditions of peroxidative stress. The profile of lipophilic aldehydes obtained for human urine resembled that for rat urine. Except for a reported 4-hydroxynon-2-enal conjugate with mercapturic acid, the conjugated forms of the lipophilic aldehydes excreted in urine remain unidentified. Aldehyde excretion is influenced by numerous factors that affect the formation of lipid peroxides in vivo such as energy status, physical activity and environmental temperature, as well as by wide variations in the intake of peroxides in the diet. Consequently, urinalysis for aldehydic products of lipid peroxidation is an unreliable indicator of the general state of peroxidative stress in vivo.