Radiotherapy, alkylating agents, and risk of bone cancer after childhood cancer.

BACKGROUND: Individuals who had cancer in childhood are at higher risk of developing bone cancer than any other type of second primary cancer. PURPOSE: Using the population-based National Registry of Childhood Tumours in Britain, we investigated the incidence and etiology of second primary bone cancer after childhood cancer in a cohort study and in a case-control study. METHODS: A cohort study of 13,175 3-year survivors of childhood cancer diagnosed in Britain between 1940 and 1983 revealed 55 subsequent bone cancers. A largely nested case-control study comprised 59 case subjects developing second primary bone cancer, and 220 control subjects were selected and matched for sex, type of first cancer, age at first cancer, and interval between diagnosis of first cancer and subsequent bone cancer. Outcome measures were the incidence of bone cancer after childhood cancer, the cumulative dose of radiation received at the site of the second cancer in the case subject and at the corresponding anatomic site in the matched control subjects, and the cumulative dose of alkylating agents and vinca alkaloids received by case and control subjects. RESULTS: The percentage of 3-year survivors developing bone cancer within 20 years did not exceed 0.9%, except following heritable retinoblastoma (7.2%), Ewing's sarcoma (5.4%), and other malignant bone tumors (2.4%). The risk of bone cancer increased substantially with increased cumulative dose of radiation to the bone (P< .001, linear trend). At the highest levels of exposure, however, the risk appeared to decline somewhat (P=.065, nonlinearity). Exposure to less than 10 Gy was at worst, associated with only a small increased relative risk (RR) of bone cancer (RR= 0.7; 95% confidence interval = 0.2-2.2). The risk of bone cancer increased linearly (P= .04, one-tailed test) with increased cumulative dose of alkylating agents. IMPLICATIONS: This population-based study provides grounds for reassurance of the majority of survivors in that their risk of developing bone cancer within 20 years of 3-year survival did not exceed 0.9%. The higher risks found for bone cancer following the other specific rare types of childhood cancer provide a rational basis for surveillance. The RRs reported for bone cancer after specified levels of exposure to radiation should help in making decisions concerning future treatment protocols.

Central injection of 5-hydroxytryptamine reduces food intake in obese and lean mice.

The effects of intracerebroventricular (ICV) administration of 5-hydroxytryptamine creatinine sulphate complex (5-HT), 35-140 nmol, on food intake in genetically obese (ob/ob) and lean mice were investigated. 5-HT (70-140 nmol) decreased feeding in a dose-related manner on 1 h and 2 h postinjection measures. Intake in lean mice was reduced by over 70% of the control condition. Obese mice, however, demonstrated a reduced sensitivity to the anorectic effect of 5-HT, and reduced 1 h intake by only 40% of saline control. Although these results are consisted with a role for serotonin in the control of food intake in mice, the altered sensitivity of the ob/ob to serotonergic stimulation may result, in part, from an impaired satiety control mechanism in this mutant.

Potentiation of dark onset feeding in obese mice (genotype ob/ob) following central injection of norepinephrine and clonidine.

Central monoaminergic neurotransmitters have been implicated in the control of food intake in different animal species but it remains unclear whether these same neurochemical systems effectively regulate feeding behaviour in the genetically obese (ob/ob) mouse. Neuropharmacological studies have demonstrated, for example, that microinjection of norepinephrine can elicit a reliable feeding response in the rat, particularly at dark onset. The present study was therefore designed to examine the impact of central injection of norepinephrine (20-160 nmol) and clonidine (5-80 nmol), an alpha 2-adrenoceptor agonist, on food intake in ob/ob mice and lean (+/?) controls. Presatiated obese and lean mice were injected with norepinephrine or clonidine immediately prior to the onset of the dark cycle. Food intake (kcal) was measured 1 h postinjection. Obese mice ingested more food than lean mice under baseline saline conditions. Injection of norepinephrine and clonidine increased eating in both phenotypes, although the ob/ob showed an enhanced feeding response to norepinephrine and clonidine administration. Intracerebroventricular pretreatment with the alpha 2-adrenoceptor antagonist yohimbine (12.5-50 nmol) significantly attenuated the increase in food intake observed in response to central injection of norepinephrine (40 nmol) and clonidine (10 nmol). However, the alpha 1-adrenoceptor antagonist corynanthine (15-60 nmol) or the beta-adrenoceptor antagonist propranolol (25-100 nmol) failed to alter noradrenergic feeding. These results suggest that modification of central alpha 2-noradrenergic function can alter natural feeding in mice, and that the ob/ob is particularly sensitive to this effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Fertilization of human oocytes in relation to varying delay before insemination.

Fertilization and pregnancy rates in an in vitro fertilization and embryo transfer program were studied after a range of insemination times of between 1 and 26 hours after oocyte recovery. There was no significant variation in fertilization rate across this range. The pregnancy rate showed no significant variation for insemination between 3 and 16 hours after aspiration. However, it was disappointing at 2 hours (3%), and no pregnancies were achieved from the nine patients whose ova were inseminated 20 or more hours after aspiration. It is concluded that mature oocytes can be inseminated in vitro at any time between 3 and 16 hours after aspiration and still retain the same potential to produce a pregnancy.

Prenatal factors in the aetiology of testicular cancer: an epidemiological study of childhood testicular cancer deaths in Great Britain, 1953-73.

A case-control study is reported based on 87 deaths from testicular cancer that occurred in children in Great Britain 1953-73. Factors that significantly increased relative risk were tuberculosis of the mother during the index pregnancy and maternal epilepsy; factors that increased risk but not significantly were hyperemesis in the index pregnancy, a maternal history of stillbirths, and hernia and genitourinary defects in the child. Cryptorchidism was not studied. The available evidence suggests that prenatal determinants of testicular cancer in adults are also determinants of testicular cancer in childhood. The incidence and mortality from this disease are not increasing among children in Britain and other countries, whereas there is an increasing trend in young adults in several developed countries. Probably, therefore, the secular increase in the rates of young adult testicular cancer is due to factors that affect adults but not children, the hence are likely to be postnatal.

Parental occupations and cancer: a review of the literature.

Parental occupation is a suspected risk factor in the occurrence of childhood cancer. Fourteen epidemiological studies investigating a possible association are reviewed and observations are found to be contradictory. Several reports show significant associations for occupations involving exposure to hydrocarbons, lead or chemicals and occupations of social classes I and II. Conversely, some studies find no association at all. Methodological variations do not account for the contrasting results so further investigation is required.

Thermal preference behavior of genetically obese (ob/ob) and genetically lean (+/?) mice.

Chronically lower colonic temperatures (TcS) of genetically-obese (ob/ob) mice at ambient temperatures below thermoneutrality have led to speculation that these mutants regulate a lowered thermal setpoint relative to lean mice. Previous experiments, however, have not provided an opportunity for obese mice to exhibit compensatory thermoregulatory behaviors which might reinstate normal body temperature. In the present experiment, adult obese and lean (+/?) mice were tested at room temperature (25 degrees C) on a copper bar, thermal gradient to determine what temperatures they would select and what effect their selection would have on their TcS. The data revealed that ob/obs were more frequently observed within 25-35 degrees C locales than were lean controls, which spent more time in the below-25 degrees C zone (p less than 0.005). Ob/obs also raised their TcS to pretest values of leans' TcS, although ob/obs' TcS remained significantly lower than those of leans at the conclusion of testing. These data suggest that the hypothermia exhibited by the ob/ob may reflect both the absence of the opportunity to behaviorally thermoregulate and a genetic defect in thermogenesis.

Thermal preference behavior in preweaning genetically obese (ob/ob) and lean (+/?, +/+) mice.

Impaired nonshivering thermogenesis and lowered rectal temperatures (Tre) are hallmarks that appear early in the postnatal ontogeny of the genetically obese (ob/ob) mouse. Adult obese mice compensate behaviorally for these impairments and do not defend their low Tres. We predicted that, because young mice primarily rely on behavior to ensure thermal homeostasis during preweaning development, the appearance of the obese mouse's thermoregulatory impairment should promote their continued reliance on behavioral thermoregulation compared to lean pups. Accordingly, intact litters of pups from heterozygous lean (C57BL/6J, ob/+) and from homozygous lean (+/+) matings were tested at 6, 12, and 18 days postpartum on a thermal gradient (14-44 degrees C). Obese pups had lower pretest Tres than lean (+/?) littermates at 6 days and lower pretest Tres than both lean littermates and homozygous (+/+) lean control pups at 12 and 18 days. Exposure to the gradient ameliorated these differences (i.e., no posttest Tre differences among phenotypes). Correspondingly, obese pups preferred warmer gradient locations than +/+ pups but similar locations to their phenotypically lean (+/?) littermates until 18 days, when both lean groups preferred similar thermal locations compared to warmer-seeking obese pups. These data support our hypothesis and emphasize the age-dependent impact of the ob gene on altering mouse pups' thermal preferences.

Milk intakes of genetically obese (ob/ob) and lean mouse pups differ with enhanced milk supply.

Although obese (C57Bl/6J, ob/ob) pups have greater avidity for nonnutritive suckling than leans as early as 15 days postpartum, previous research has not found differences in milk intake between ob/ob and lean mice during the preweaning period. Because ob/ob pups suckle longer than leans, their perseveration should enhance their opportunity to ingest milk if (a) maternal milk supply is not limited and (b) longer sucking durations reflect increased pup willingness to ingest milk. Accordingly, the present study was designed to evaluate the milk intake of ob/ob and lean pups when they had access to an enhanced supply of maternal milk. Intact litters of pups, from heterozygous lean (ob/+) parents, were randomly assigned to be tested at either 6, 12, or 18 days. Pups were neither dam- nor milk-deprived before being cross-fostered successively to milk-replete surrogate dams for 60 min each. Obese pups showed a greater percentage body weight gain (the index of milk intake) than leans did, with younger pups showing larger increments than 18-day-olds. Although early adiposity in ob/ob pups may not rely on increased intake in the single-dam, nest situation, these data emphasize an early predisposition to overeating in this mutant.

Bidirectional effects of clonidine on carbohydrate intake in genetically obese (ob/ob) mice.

Hypothalamic noradrenergic mechanisms contribute to altered caloric intake in genetically obese (C57BL/6J, ob/ob) mice. Noradrenergic mechanisms, principally in the paraventricular hypothalamus and of the alpha 2 subtype, have also been implicated in the macronutrient intake regulation of nonpathological models. Accordingly, this study assessed the extent to which clonidine, an alpha 2 agonist, altered macronutrient intake in genetically obese (ob/ob) and lean (C57BL/6J, +/?) mice. Following adaptation to a 6-h feeding regimen, mice were injected intraperitoneally with either clonidine (0.1, 0.5 mg/kg) or 0.15 M NaCl (Experiment 1) or 0.025 mg/kg clonidine or saline (Experiment 2) 30 min prior to simultaneous access to separate sources of carbohydrate, fat, and protein. Clonidine doses of 0.1 mg/kg or greater reduced total energy intake and intake of carbohydrate and fat (p less than 0.005) in all mice (Experiment 1). However, 0.025 mg/kg clonidine selectively increased ingestion of carbohydrate in obese mice by 212% of vehicle-injected values (p less than 0.001) without altering intake in lean mice (Experiment 2). These results implicate an alpha 2 receptor mechanism in genetic obesity.

Yohimbine attenuates clonidine-induced feeding and macronutrient selection in genetically obese (ob/ob) mice.

Biochemical abnormalities in the hypothalamus of the genetically obese (C57B1/6J, ob/ob) mouse, including increased levels of endogenous norepinephrine (NE) in the paraventricular nucleus (PVN) and reduced medial hypothalamic NE metabolism, have been cited as evidence of a CNS defect contributing to altered caloric intake in this genetic strain. In the current study, the alpha 2-antagonist yohimbine (YOH) and the alpha 2-agonist clonidine (CLON) were administered systemically to 6-h meal-feeding obese and lean mice. Yohimbine (3-5 mg/kg, IP) significantly reduced total energy intake and intake of carbohydrate and fat, in both phenotypes, without altering protein intake. In contrast, CLON (25 micrograms/kg, IP) potentiated feeding, resulting in a shift in macronutrient selection toward a significant increase in the proportional intake of carbohydrate. Obese mice, however, showed an enhanced behavioral response to CLON injection. Pretreatment with 1 mg/kg YOH, a dose that alone did not significantly alter energy intake or diet selection, blocked CLON's stimulatory effect on feeding and carbohydrate preference. These results are consistent with a role for alpha 2-noradrenergic receptors in appetite regulation of ob/ob and lean mice and suggest that disturbances in this system may be involved in the development of genetic obesity.

Role of inertia in two-dimensional deformation and breakdown of a droplet.

We investigate by lattice Boltzmann methods the effect of inertia on the deformation and breakdown of stability of a two-dimensional fluid droplet surrounded by fluid of equal viscosity (in a confined geometry) whose shear rate is increased very slowly. We give evidence that in two dimensions inertia is necessary for the loss of stability, so that at zero Reynolds number there is always a stable stationary droplet shape. We identify two different routes to breakdown, via two-lobed and three-lobed structures and give evidence for a sharp transition between these routes as parameters are varied.

Effect of T-2 toxin on brain biogenic monoamines in rats and chickens.

Two experiments were conducted to determine the effect of T-2 toxin on brain biogenic monoamines and their metabolites. Male rats (180 g) and cockerels (28 day, 300 g) were orally dosed with T-2 toxin at 2.5 mg kg-1 body weight. In the first experiment, whole brains were collected 2, 6, 12, 24 and 48 h postdosing and analyzed for monoamines by high performance liquid chromatography with electro-chemical detection. T-2 toxin did not influence whole brain concentrations of monoamines in either species. In the second experiment, brains were collected 24 h postdosing, dissected into five brain regions, and analyzed for monoamines. T-2 toxin treatment resulted in increased serotonin and 5-hydroxy-3-indoleacetic acid in all brain regions of the rat. However, this was not seen in poultry where T-2 toxin treatment resulted in an increase in 5-hydroxy-3-indoleacetic acid, no alteration in serotonin concentration and a decrease in regional norepinephrine and dopamine concentrations. These results suggest that T-2 toxin influences brain biogenic amine metabolism and that there is an intraspecies difference in the central effects of this mycotoxin.

Dialectic thinking as a means of understanding systems-in-development: relevance to Rogers's principles.

This paper explores the dialectical noncausal category of determination as a method of explaining human development and examines its relationship to Rogers's principles of homeodynamics. The relationships among determinism, causality, and lawfulness are discussed, and the categories of determination are reviewed.

Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

OBJECTIVE: To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN: Cohort study and a case-control study. SETTING: Britain and population based National Register of Childhood Tumours. SUBJECTS: Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES: Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS: Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS: Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer.