Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes

Recent studies have demonstrated that in the absence of spleen function, frequencies of micronuclei (Howell-Jolly bodies) in peripheral blood rbcs can be used to measure in vivo cytogenetic damage. Among 20 subjects studied greater than or equal to 6 months after splenectomy, 1 had a frequency of micronucleated rbcs more than an order of magnitude higher than rates for the others. Initial data suggested that this subject was mildly folate-depleted, and a therapeutic trial with folate rapidly reduced the frequency of micronucleated rbcs to normal values. These observations suggest a need to evaluate further the contribution of mild levels of folate depletion to spontaneous chromosomal damage. The approach used here provides a sensitive index of clastogenic damage and offers unique opportunities for investigating the determinants of cytogenetic damage in humans.     

Smoking-related alterations in epidermal growth factor and insulin receptors in human placenta

Studies characterized insulin and EGF receptors in human placental tissue from smokers and nonsmokers. Specific binding of 125I-labeled insulin and EGF to placental membranes was not different for nonsmokers compared with smokers. EGF and insulin receptor kinases were further studied using a wheat germ agglutinin-purified preparation of solubilized placental membrane proteins. In extracts from the nonsmoker group, EGF stimulated the active phosphorylation of Mr 170,000 and 140,000 protein bands, which was half-maximal (EC50) at 5 x 10(-8) M. In extracts from the smokers group, however, phosphorylation of these two protein bands was barely detectable over a range of 0 to 10(-6) M EGF. Thus, EGF-stimulated phosphorylation of the 170,000 and 140,000 bands was markedly decreased in placental membranes from smokers. In contrast, insulin stimulated the phosphorylation of a 95,000 protein that was immunoprecipitated with anti-insulin receptor antiserum in membrane preparations from both nonsmokers and smokers. Dose-response curves for autophosphorylation indicate that EC50 values were 2.6 and 7.0 nM insulin for nonsmokers and smokers, respectively. Laser densitometry scan of the 95,000 band on autoradiograms further showed that maximal 32P incorporation was 30% greater in smokers compared with nonsmokers. Analysis of the insulin-dependent phosphorylation of an exogenous substrate, poly(Glu,Tyr) (4:1), showed a similar pattern of values for nonsmokers versus smokers. These results indicate that insulin receptor autophosphorylation and tyrosine kinase activity were normal or increased, whereas EGF-stimulated kinase activity was markedly decreased in placental membrane proteins from smokers. Western blot analysis using an antiserum to the EGF receptor showed the presence of immunoreactive bands of 126,000 and 150,000-170,000 in receptor preparations from nonsmokers, whereas only the 126,000 protein was detected in preparations from smokers. Thus, the smoking-related deficiency in EGF receptor autophosphorylation appeared to be due to the absence of a 150,000-170,000 receptor protein. In conclusion, maternal cigarette smoking is associated with selective alterations in two major receptor-mediated pathways thought to be involved in cell growth and differentiation in human placenta.     

Protective spectacles for retinitis pigmentosa patients.

On the hypothesis that ophthalmic filters with appropriate light transmission characteristics may be beneficial in retarding the progress of retinal degeneration in early retinitis pigmentosa, the characteristics of several plastic and glass filters have been evaluated. A dark brown plastic goggle has been found which meets the theoretical criteria previously postulated for such protection. Its characteristics and those of other filters are compared with a lens which was specially designed for RP protection and was previously reported on by Adrian and Schmidt.     

Randomized clinical trial of doxorubicin alone or combined with mitolactol in women with advanced breast cancer and prior chemotherapy exposure

One hundred fifty-one women with advanced breast cancer who had failed prior chemotherapy were randomized to monthly courses of doxorubicin (60 mg/m2 I.V. day 1, observation after 500 mg/m2) or doxorubicin (40 mg/m2 I.V. day 1; maximum 500 mg/m2) and mitolactol (135 mg/m2 orally, days 1-10; 180 mg/m2 after maximum doxorubicin). Median survival times were 232 days for doxorubicin and 225 days for doxorubicin + mitolactol, and median times to progression were 112 days and 97 days, respectively. Results are inconsistent with a 25% improvement in survival or time to progression for doxorubicin + mitolactol (p = 0.04 and 0.02, respectively, adjusted for stratification factors but not multiple testing). Regression rates for all patients, both measurable and evaluable, were 30% for doxorubicin alone and 26% for doxorubicin + mitolactol. Regression rates were significantly higher in patients with measurable indicator lesions. Cardiac toxicity was seen in four patients, all of whom were receiving doxorubicin alone. It appears that the combination of doxorubicin + mitolactol is not substantially more effective than doxorubicin alone in women with advanced breast cancer and prior chemotherapy exposure.     

Cancer risk in adulthood from early life exposure to parents' smoking

We obtained data on smoking by parents from 438 cancer cases and 470 controls to investigate whether cancer risk in adult life is related to transplacental or childhood exposure to cigarette smoke. Cancer cases were between ages 15 and 59 at time of diagnosis. All sites but basal cell cancer of the skin were included. Cancer risk was increased 50 per cent among offspring of men who smoked. Increased risk associated with father's smoking was not explained by demographic factors, social class, or individual smoking habits, and was not limited to known smoking related sites. Relative risk (RR) estimates associated with father's smoking tended to be greatest for smokers, males, and non-Whites. There was only a slight increase in overall cancer risk associated with maternal smoking. Mother's and father's smoking were both associated with risk for hematopoietic cancers, and a dose-response relationship was seen. The RR for hematopoietic cancers increased from 1.7 when one parent smoked to 4.6 when both parents smoked. Although they should be considered tentative, study findings suggest a long-term hazard from transplacental or childhood passive exposure to cigarette smoke.     

Attention-deficit hyperactivity disorder and fluctuating asymmetry in another college sample.

Attention deficit/hyperactivity disorder (AD/HD) represents a developmental lag that may be reflected in fluctuating asymmetry (FA), i.e., differences from perfect symmetry in traits that display bilateral symmetry. Burton et al. (2003 Am. J. Hum. Biol. 15:601-619) found a statistical trend for FA to increase (as dermatoglyphic index or as total index) as the behavioral measure for AD/HDness (Rasch logit values derived from the Wender Utah Rating Scale, or WURS) increased in males but not in females. The objective here was to do a similar study in an independently collected sample of college students (n = 222; 61 male, 161 female) not selected for AD/HD, looking at FA vs. symptoms for AD/HD based on Rasch versions of responses to the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) (Barkley and Murphy 1998 Attention-Deficit Hyperactivity Disorder, New York: Guilford Press, p. 95-96) and the more comparable shortened WURS. FAs were lowest for body and ear height, and highest for eye width and nose width, and ranged from 0.01 +/- 0.001 (mean +/- SE) for foot and ankle widths to 0.13 +/- 0.01 in eye and nose widths for both sexes; the sexes did not differ significantly. Males displayed higher AD/HD symptom rates overall. There was a significant correlation between body FA and the WURS measure in females after Bonferroni correction (P = 0.002, r(2) = 0.058). Thus, AD/HD symptoms levels increased with an increase in body FA in female college students not selected for AD/HD.