APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Synthesis, herbicidal activity, and mode of action of IR 5790.

IR 5790, an arylthiadiazolone herbicide structurally related to oxadiargyl and oxadiazon, was synthesized. The herbicidal activity and mode of action of IR 5790 were investigated. This herbicide has broad-spectrum pre-emergence activity against both dicotyledonous and monocotyledonous weeds. The phenotypic responses of susceptible plants, such as interruption of growth and light-dependent development of necrotic areas on the foliage, are consistent with those observed with protoporphyrinogen oxidase-inhibiting herbicides. Tissues exposed to IR 5790 in darkness accumulated protoporphyrin IX, which led to a photodynamic loss of membrane integrity upon exposure to light. Consistent with these physiological symptoms, IR 5790 strongly inhibited protoporphyrinogen oxidase, with an I(50) value of 3 nM. The presence of a sulfur atom did not significantly alter the molecular properties of the thiadiazolone ring, relative to the oxadiazolone ring of oxadiargyl, which explains why IR 5790 has the same mode of action as this herbicide.

Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions.

PURPOSE: To assess the interobserver agreement on the diagnosis and classification of cutaneous melanoma. MATERIALS AND METHODS: A set of 140 slides of cutaneous melanoma, including a small subset of benign pigmented skin lesions, were circulated to four experienced histopathologists. The kappa statistic for multiple ratings per subject was calculated using the method described by Fleiss. RESULTS: The kappa value on the diagnosis of cutaneous melanoma versus benign lesions was 0.61. There was some discordance on the diagnosis in 37 of 140 cases (26%). For the histopathologic classification of cutaneous melanoma, the highest kappa values were attained for Breslow thickness (kappa = 0.76) and presence of ulceration (kappa = 0.87). The agreement was generally poor for other histologic features, such as level of dermal invasion (kappa = 0.38), presence of regression (kappa = 0.27), and lymphocytic infiltration (kappa = 0.27). CONCLUSION: Our study suggests considerable disagreement among pathologists on the diagnosis of melanoma versus other pigmented lesions. Tumor thickness and presence of ulceration are the most reproducible histologic features of cutaneous melanoma.

Effect of estrogens on dopamine autoreceptors in male rats.

There is biochemical and pharmacological evidence indicating that estrogens are capable of substantially modulating post-synaptic dopamine (DA) receptor sensitivity in experimental animals. Recent electrophysiological data, showing that estrogens significantly attenuate the ability of apomorphine to inhibit the firing activity of type B dopamine neurons in the rat substantia nigra, suggest that these hormones may also induce subsensitivity of DA autoreceptors. In accord with this hypothesis, estrogen-treated rats showed no marked decrease of motility counts when challenged with apomorphine (20-50 micrograms/kg) from 24 to 72 h after the last hormone administration. Similarly, the decrease of dihydroxyphenylacetic acid (DOPAC) levels induced by apomorphine (20 micrograms/kg) in the caudate nucleus, in oil-treated control rats was almost completely counteracted by estrogen treatment. Dopamine agonists, such as 2-alpha-bromocriptine, piribedil, 3 hydroxyphenylpropylpiperidine and n-propylnorapomorphine, failed to induce hypomotility when administered to estrogen-treated rats. These behavioural and biochemical results, along with the electrophysiological data, indicate that estrogen treatment is able to induce hyposensitivity of DA autoreceptors. These results may be relevant to the clinical findings indicating that the activity of dopamine receptor agonists varies in relation to sex or hormonal treatments.

Sex pheromone components of the European goat moth,Cossus cossus.

Female tip washings of the European goat moth,Cossus cossus L., were found to contain the following compounds that are structurally similar to known pheromone components of Lepidoptera (%): decyl acetate (1.5), (Z)-5-dodecenol (1), (Z)-5-dodecenyl acetate (66), dodecyl acetate (12), (Z)-5-tetradecenyl acetate (14), tetradecyl acetate (4), and hexadecyl acetate (1.5). The washes contained an average of 125 ng of (Z)-5-dodecenyl acetate per female equivalent. EAG responses to nanogram amounts of the identified products indicated that (Z)-5-dodecenyl acetate was the most potent olfactory stimulant followed by (Z)-5-tetradecenyl acetate and (Z)-5-dodecenol, whereas the saturated acetates caused only weak depolarization. A strong EAG response was also recorded for (Z)-3-decenyl acetate, which was not detected in the female tip washings. Field results showed that (Z)-5-dodecenyl acetate was essential for the attraction of the males and that (Z)-3-decenyl acetate improved the attractiveness of (Z)-5-dodecenyl acetate alone or in combination with (Z)-5-tetradecenyl acetate.