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Biomedical subjects

R Doll

Publications and source records attributed to R Doll.

At least 73 records · Page 4Linked to original sources
PubMed1997

Risk of childhood cancer from fetal irradiation.

The association between the low dose of ionizing radiation received by the fetus in utero from diagnostic radiography, particularly in the last trimester of pregnancy, and the subsequent risk of cancer in childhood provides direct evidence against the existence of a threshold dose below which no excess risk arises, and has led to changes in medical practice. Initially reported in 1956, a consistent association has been found in many case-control studies in different countries. The excess relative risk obtained from combining the results of these studies has high statistical significance and suggests that, in the past, a radiographic examination of the abdomen of a pregnant woman produced a proportional increase in risk of about 40%. A corresponding causal relationship is not universally accepted and this interpretation has been challenged on four grounds. On review, the evidence against bias and confounding as alternative explanations for the association is strong. Scrutiny of the objections to causality suggests that they are not, or may not be, valid. A causal explanation is supported by evidence indicating an appropriate dose-response relationship and by animal experiments. It is concluded that radiation doses of the order of 10 mGy received by the fetus in utero produce a consequent increase in the risk of childhood cancer. The excess absolute risk coefficient at this level of exposure is approximately 6% per gray, although the exact value of this risk coefficient remains uncertain.

Adolescent↗
PubMed1996

Nature and nurture: possibilities for cancer control.

Nature and nurture interact and in most cases it is impossible to specify quantitatively the contribution of either to the causation of a disease. Only rarely is either neutral in the sense that the other accounts for all the variation in risk. It seems unlikely that more than a few per cent of all cancers will be accounted for by inherited susceptibility with a high penetrance and a neutral environment. Small variations in susceptibility may, however, be associated with different genetic alleles that will facilitate focused measures of prevention and perhaps provide a lead to causation. For the practical control of most cancers we must intervene by treatment or prevention. Knowledge of the variation in the incidence of cancers suggests that age-specific incidence rates could be reduced by 80-90%, half by the application of existing knowledge. The possibilities of control by prevention are discussed under the headings of tobacco smoke, alcohol, infection, diet, physical activity, reproduction, medicines and medical procedures, and occupation and pollution. In conclusion, attention is drawn to eight types of cancer that have become more common in the UK in the last 25 years, some of which we do not know how to prevent and which require urgent research.

Alcohol Drinking↗
PubMed1996

Mortality from smoking worldwide.

Estimates are made of the numbers and proportions of deaths attributable to smoking in 44 developed countries in 1990. In developed countries as a whole, tobacco was responsible for 24% of all male deaths and 7% of all female deaths, rising to over 40% in men in some former socialist economies and 17% in women in the USA. The average loss of life for all cigarette smokers was about 8 years and for those whose deaths were attributable to tobacco about 16 years. Trends in mortality attributable to tobacco differed between countries. In some the mortality in middle age (35-69 years) had decreased by half in men since 1965; in others it was continuing to increase. In women, the proportion was mostly increasing, almost universally in old age. Mortality not attributable to smoking decreased since 1955 in all OECD (Organization for European Collaboration and Development) countries, by up to 60% in men and more in women. No precise estimate can be made of the number of deaths attributable to smoking in undeveloped countries, but the prevalence of smoking suggests that it will be large. In the world as a whole, some 3 million deaths a year are estimated to be attributable to smoking, rising to 10 million a year in 30-40 years' time.

Adolescent↗
PubMed1996

Cancers weakly related to smoking.

In 1985, review of the carcinogenic effects of tobacco led the International Agency for Research on Cancer to conclude that the smoking of cigarettes was an important cause of cancers of the lung, larynx, oro- and hypo-pharynx, oesophagus, bladder, renal pelvis, and pancreas and that the smoking of tobacco in other form was also an important cause of some of them. More evidence about common cancers has now been obtained in cohort studies and about less common cancers in case-control studies. Many are weakly related to smoking. Review now justifies the conclusion that cigarette smoking is also a cause of cancers of the stomach, renal body, liver, and nose and of myeloid leukaemia and may be a cause of cancers of the nasopharynx and lip, and that pipe smoking is a cause of cancer of the lip. Associations between cigarette smoking and cancers of the large bowel and cervix uteri may be largely, and perhaps wholly, explained by confounding.

Adenocarcinoma↗
PubMed1995

Novel tricyclic inhibitors of farnesyl protein transferase. Biochemical characterization and inhibition of Ras modification in transfected Cos cells.

Ras protooncogenes encode 21-kDa membrane-associated guanine nucleotide-binding proteins, which play a critical role in control of cellular proliferation and differentiation. Oncogenic, activated forms of Ras proteins are associated with a broad range of human cancers. The elucidation of the post-translational modifications that occur at the carboxyl terminus of Ras and the demonstration that farnesylation of Ras by farnesyl protein transferase is essential for Ras-induced cellular transformation has opened up a new and promising approach to the development of anti-Ras therapeutics. We report here a novel series of potent farnesyl protein transferase (FPT) inhibitors, represented by SCH 44342. This compound inhibits both rat brain and recombinant human FPT with an IC50 of approximately 250 nM, while it is only weakly active against rat brain geranylgeranyl protein transferase-1 (IC50 > 114 microM). FPT inhibition has been observed using both Ha-Ras protein and Ki-Ras-derived peptide substrates in two different assay formats. SCH 44342 and its analogs also inhibit farnesylation of Ras in Cos cells transiently expressing [Val12]Ha-Ras with IC50 values in the low micromolar range. At these concentrations they do not inhibit sterol biosynthesis or geranylgeranylation of protein. In addition, we observed that Cos cells undergo pronounced morphological changes upon overexpression of [Val12]activated forms of Ha-Ras containing COOH-terminal sequences allowing farnesylation (CVLS) or geranylgeranylation (CVLL) but not upon overexpression of activated Ras lacking the isoprenylated Cys (SVLS). Ras-induced morphological changes can be partially reverted with lovastatin. Importantly, SCH 44342 can block morphological changes induced by [Val12]Ha-Ras-CVLS but not [Val12]Ha-Ras-CVLL. Recently, a number of other FPT inhibitors have been reported. Most of the compounds reported to have cell-based activity are peptidomimetic analogs of the CAAX substrate. Our FPT inhibitors are novel in that although they compete with Ras protein in kinetic experiments they are entirely nonpeptidic in nature, they do not have oxidizable sulfhydryl functions, and they are active in cells at low micromolar concentrations.

Alkyl and Aryl Transferases↗
PubMed1995

Hazards of ionising radiation: 100 years of observations on man.

In November 1895, when Conrad Röntgen serendipitously discovered X-rays, epidemiology was effectively limited to the study of infectious disease. What little epidemiological work was done in other fields was done as part of clinical medicine or under the heading of geographical pathology. The risks from exposure to X-rays and subsequently from other types of ionising radiation were consequently discovered by qualitative association or animal experiment. They did not begin to be quantified in humans until half a century later, when epidemiology emerged as a scientific discipline capable of quantifying risks of non-infectious disease and the scientific world was alerted to the need for assessing the effects of the radiation to which large populations might be exposed by the use of nuclear energy in peace and war.

Abnormalities, Radiation-Induced↗
PubMed1995

Chronic and degenerative disease: major causes of morbidity and death.

In OECD (Organization for Economic Cooperation and Development) countries (Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Japan, Luxembourg, Netherlands, New Zealand, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom, and United States), mortality at ages 35-69 y has fallen by 38% since 1955 and the risk of dying before age 70 y has been reduced to 23%. In middle and old age, chronic and degenerative diseases are the principal causes of death. Neoplasms, ischemic heart disease, and cerebrovascular disease cause three-quarters of all deaths at 35-69 y of age and two-thirds at older ages. Mortality from vascular disease has declined rapidly. Mortality from neoplasms has not declined rapidly; however, mortality not attributed to smoking has and there is no general increase in cancer attributable to industrial development. Despite lower death rates in nonsmokers than in cigarette smokers, vascular disease and neoplasms remain the targets for prevention. With increased duration of life, conditions that cause serious disability in old age become more important and the principal foci for research. These conditions are also chronic and degenerative.

Cause of Death↗
PubMed1995

Occupational exposure to hydrazine and subsequent risk of cancer.

OBJECTIVES: The aim was to examine the cause specific mortality of men exposed to hydrazine. METHODS: Hydrazine was produced at a factory in the east midlands between 1945 and 1971. The cohort of all 427 men who were employed there for at least six months with varying degrees of occupational exposure to hydrazine were followed up until the end of January 1992. RESULTS: By the end of July 1982 49 deaths had occurred and the observed mortality was found to be close to that expected at each level of exposure. By the end of January 1992 a further 37 deaths had occurred. Again the observed mortality was close to that expected for all causes and also for lung cancer, cancers of the digestive system, other cancers, and all other causes, irrespective of the level of exposure. CONCLUSIONS: The results weigh against there having been any material hazard of occupational exposure to hydrazine. The small number of men studied means, however, that a relative risk as high as 3.5 for lung cancer cannot confidently be excluded.

Cause of Death↗
PubMed1995

Leukemia mortality after X-ray treatment for ankylosing spondylitis.

Leukemia mortality has been studied in 14,767 adult ankylosing spondylitis patients diagnosed between 1935 and 1957 in the United Kingdom, of whom 13,914 patients received X-ray treatment. By 1 January 1992, there were 60 leukemia deaths among the irradiated patients, almost treble that expected from national rates. Leukemia mortality was not increased among unirradiated patients. Among those irradiated, the ratio of observed to expected deaths for leukemia other than chronic lymphocytic leukemia was greatest in the period 1-5 years after the first treatment (ratio = 11.01, 95% confidence interval 5.26-20.98) and decreased to 1.87 (95% confidence interval 0.94-3.36) in the 25+ year period. There was no significant variation in this ratio with sex or age at first treatment. The ratio for chronic lymphocytic leukemia was slightly but not significantly raised (ratio = 1.44, 95% confidence interval 0.62-2.79). Most irradiated patients received all their exposure within a year. Based on a 1 in 15 random sample, the mean total marrow dose was 4.38 Gy. Doses were nonuniform, with heaviest doses to the lower spine. The risk for nonchronic lymphocytic leukemia was adequately described by a linear-exponential model that allowed for cell sterilization in heavily exposed parts of the marrow and time since exposure. Ten years after first exposure, the linear component of excess relative risk was 12.37 per Gy (95% confidence interval 2.25-52.07), and it was estimated that cell sterilization reduced the excess relative risk by 47% at 1 Gy (95% confidence interval 17%-79%). The average predicted relative risk in the period 1-25 years after exposure to a uniform dose of 1 Gy was 7.00.

Adult↗
PubMed1994

Cancer mortality following X-ray treatment for ankylosing spondylitis.

Mortality has been studied in 15,577 ankylosing spondylitis (AS) patients diagnosed between 1935 and 1957 in the UK, of whom 14,556 received X-ray treatment. By January 1, 1992 over half of the cohort had died. Among the irradiated patients, cancer mortality was significantly greater than expected from the national rates for England and Wales, with a ratio of observed deaths to expected (relative risk, RR) of 1.30, and significant increases individually for leukaemia, non-Hodgkin's lymphoma, multiple myeloma and cancers of the oesophagus, colon, pancreas, lung, bones, connective and soft tissue, prostate, bladder and kidney. Among the unirradiated patients, cancer mortality was lower than expected from national rates (RR = 0.79). Among irradiated patients, the RRs for leukaemia, lung cancer, and all other neoplasms all decreased significantly with increasing time since first treatment following an initial increase. By 35 years after first treatment, the radiation-related excess for lung cancer had completely disappeared, while for other neoplasms the RR remained significantly raised, although at a lower level than in earlier periods. Most irradiated patients received several courses of treatment within a 5-year period. Based on a 1 in 15 random sample, the mean total body dose received in this period was 2.64 Gy, with the heaviest dose to the vertebrae. A linear dose-response model for all neoplasms except leukaemia gave an excess RR of 0.18 Gy-1 in the period 5-24.9 years after first treatment, which decreased significantly to 0.11 Gy-1 in the period more than 25 years after first treatment. There was no evidence that a linear-quadratic model fitted the data better than a linear model. There were significant dose-response relationships individually for cancers of the lung, oesophagus, colon, pancreas, prostate, bladder and kidney.

Adult↗
PubMed1994

Mortality in relation to smoking: 40 years' observations on male British doctors.

OBJECTIVE: To assess the hazards associated with long term use of tobacco. DESIGN: Prospective study of mortality in relation to smoking habits assessed in 1951 and again from time to time thereafter, with causes sought of deaths over 40 years (to 1991). Continuation of a study that was last reported after 20 years' follow up (1951-71). SUBJECTS: 34,439 British male doctors who replied to a postal questionnaire in 1951, of whom 10,000 had died during the first 20 years and another 10,000 have died during the second 20 years. RESULTS: Excess mortality associated with smoking was about twice as extreme during the second half of the study as it had been during the first half. The death rate ratios during 1971-91 (comparing continuing cigarette smokers with life-long non-smokers) were approximately threefold at ages 45-64 and twofold at ages 65-84. The excess mortality was chiefly from diseases that can be caused by smoking. Positive associations with smoking were confirmed for death from cancers of the mouth, oesophagus, pharynx, larynx, lung, pancreas, and bladder; from chronic obstructive pulmonary disease and other respiratory diseases; from vascular diseases; from peptic ulcer; and (perhaps because of confounding by personality and alcohol use) from cirrhosis, suicide, and poisoning. A negative association was confirmed with death from Parkinson's disease. Those who stopped smoking before middle age subsequently avoided almost all of the excess risk that they would otherwise have suffered, but even those who stopped smoking in middle age were subsequently at substantially less risk than those who continued to smoke. CONCLUSION: Results from the first 20 years of this study, and of other studies at that time, substantially underestimated the hazards of long term use of tobacco. It now seems that about half of all regular cigarette smokers will eventually be killed by their habit.

Adult↗
PubMed1994

Mortality in relation to consumption of alcohol: 13 years' observations on male British doctors.

OBJECTIVE: To assess the risk of death associated with various patterns of alcohol consumption. DESIGN: Prospective study of mortality in relation to alcohol drinking habits in 1978, with causes of death sought over the next 13 years (to 1991). SUBJECTS: 12,321 British male doctors born between 1900 and 1930 (mean 1916) who replied to a postal questionnaire in 1978. Those written to in 1978 were the survivors of a long running prospective study of the effects of smoking that had begun in 1951 and was still continuing. RESULTS: Men were divided on the basis of their response to the 1978 questionnaire into two groups according to whether or not they had ever had any type of vascular disease, diabetes, or "life threatening disease" and into seven groups according to the amount of alcohol they drank. By 1991 almost a third had died. All statistical analyses of mortality were standardised for age, calendar year, and smoking habit. There was a U shaped relation between all cause mortality and the average amount of alcohol reportedly drunk; those who reported drinking 8-14 units of alcohol a week (corresponding to an average of one to two units a day) had the lowest risks. The causes of death were grouped into three main categories: "alcohol augmented" causes (6% of all deaths: cirrhosis, liver cancer, upper aerodigestive (mouth, oesophagus, larynx, and pharynx) cancer, alcoholism, poisoning, or injury), ischaemic heart disease (33% of all deaths), and other causes. The few deaths from alcohol augmented causes showed, at least among regular drinkers, a progressive trend, with the risk increasing with dose. In contrast, the many deaths from ischaemic heart disease showed no significant trend among regular drinkers, but there were significantly lower rates in regular drinkers than in non-drinkers. The aggregate of all other causes showed a U shaped dose-response relation similar to that for all cause mortality. Similar differences persisted irrespective of a history of previous disease, age (under 75 or 75 and older), and period of follow up (first five and last eight years). Some, but apparently not much, of the excess mortality in non-drinkers could be attributed to the inclusion among them of a small proportion of former drinkers. CONCLUSION: The consumption of alcohol appeared to reduce the risk of ischaemic heart disease, largely irrespective of amount. Among regular drinkers mortality from all causes combined increased progressively with amount drunk above 21 units a week. Among British men in middle or older age the consumption of an average of one or two units of alcohol a day is associated with significantly lower all cause mortality than is the consumption of no alcohol, or the consumption of substantial amounts. Above about three units (two American units) of alcohol a day, progressively greater levels of consumption are associated with progressively higher all cause mortality.

Adult↗
PubMed1994

Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d).

The structure of the metalloproteinase and hemorrhagic toxin atrolysin C form d (EC 3.4.24.42), from the venom of the western diamondback rattlesnake Crotalus atrox, has been determined to atomic resolution by x-ray crystallographic methods. This study illuminates the nature of inhibitor binding with natural (< Glu-Asn-Trp, where < Glu is pyroglutamic acid) and synthetic (SCH 47890) ligands. The primary specificity pocket is exceptionally deep; the nature of inhibitor and productive substrate binding is discussed. Insights gained from the study of these complexes facilitate the design of potential drugs to treat diseases where matrix metalloproteinases have been implicated, e.g., arthritis and tumor metastasis.

Amides↗