Molecular biology and genetics of Alzheimer's disease

The recent progress in molecular biology research has changed the past concepts on Alzheimer's disease (AD) and other nervous system amyloidoses. This paper compiles the basic principles of molecular biology of AD and reviews their clinical impact The new data about the function and metabolism of amyloid precursor protein and the more recent information on the role of the apolipoprotein E have provided new insight into the pathogenesis of this disease. Although further investigations are still required to assemble these data into a theory that completely explains the development of the disease and changes the present symptomatic therapeutic strategies to an entire preventive or curative approach, the recent research results in this field are relevant for the diagnostic and therapeutic management of AD patients.     

Enzymes involved in the bioactivation of 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone in patas monkey lung and liver microsomes

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogen in animals. Our previous studies indicated that there are differences between rodents and humans for the enzymes involved in the activation of NNK. To determine if the patas monkey is a better animal model for the activation of NNK in humans, we investigated the metabolism of NNK in patas monkey lung and liver microsomes and characterized the enzymes involved in the activation. In lung microsomes, the formation of 4-oxo-1-(3-pyridyl)-1-butanone (keto aldehyde), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK- N-oxide), 4-hydroxy-1-(3-pyridyl)-1-butanone (keto alcohol), and 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) was observed, displaying apparent Km values of 10.3, 5.4, 4.9, and 902 microM, respectively. NNK metabolism in liver microsomes resulted in the formation of keto aldehyde, keto alcohol, and NNAL, displaying apparent Km values of 8.1, 8.2, and 474 microM, respectively. The low Km values for NNK oxidation in the patas monkey lung and liver microsomes are different from those in human lung and liver microsomes showing Km values of 400-653 microM, although loss of low Km forms from human tissue as a result of disease, surgery or anesthesia cannot be ruled out. Carbon monoxide (90%) significantly inhibited NNK metabolism in the patas monkey lung and liver microsomes by 38-66% and 82-91%, respectively. Nordihydroguaiaretic acid (a lipoxygenase inhibitor) and aspirin (a cyclooxygenase inhibitor) decreased the rate of formation of keto aldehyde and keto alcohol by 10-20 % in the monkey lung microsomes. Alpha-Napthoflavone and coumarin markedly decreased the oxidation of NNK in monkey lung and liver microsomes, suggesting the involvement of P450s 1A and 2A6. An antibody against human P450 2A6 decreased the oxidation of NNK by 12-16% and 22-24% in the patas monkey lung and liver microsomes, respectively. These results are comparable to that obtained with human lung and liver microsomes. Coumarin hydroxylation was observed in the patas monkey lung and liver microsomes at a rate of 16 and 4000 pmol/min/mg protein, respectively, which was 5-fold higher than human lung and liver microsomes, respectively. Immunoblot analysis demonstrated that the P450 2A level in the individual patas monkey liver microsomal sample was 6-fold greater than in an individual human liver microsomal sample. Phenethyl isothiocyanate, an inhibitor of NNK activation in rodents and humans, decreased NNK oxidation in the monkey lung and liver microsomes displaying inhibitor concentration resulting in 50% inhibition of the activity (IC50) values of 0.28-0.8 microM and 4.2-6.8 microM, respectively. The results demonstrate the similarities and differences between species in the metabolic activation of NNK. The patas monkey microsomes appear to more closely resemble human microsomes than mouse or rat enzymes and may better reflect the activation of NNK in humans.      

Promotion of dimethylbenz[a]anthracene-initiated mammary carcinogenesis by iron in female Sprague-Dawley rats

Iron body-stores and iron dietary intake have been sporadically reported to increase the risk of cancer in humans. To investigate the effect of iron on the development of mammary tumors, female Sprague- Dawley rats were given dimethylbenz[a]anthracene (DMBA) (5 mg/kg, i.g., 1x) at 55 days of age. Eight days later, rats received iron(II) sulfate s.c. (50 micromol/kg, 2x/week) for 53 weeks. Mammary tumors started to appear 6-8 weeks after DMBA initiation. At 20 weeks after DMBA treatment, iron(II) increased mammary tumor frequency twofold (11/30 versus 5/30 with DMBA alone). Tumor frequency increased with time and was significantly higher in iron-promoted rats after 40 weeks of treatment (24/30 versus 11/30, P = 0.001). Also, mammary tumors in iron- promoted rats were significantly larger than in DMBA-only rats at 20 weeks after initiation (P = 0.04) and this difference remained significant through the observation time point at 40 weeks. Iron could be detected histochemically in the stromal connective tissue, but not in the epithelial cells of mammary carcinomas. Mammary tumors in the DMBA-only group were mostly adenomas and adenocarcinomas, while those promoted by iron sulfate included fibroadenomas, adenomas and adenocarcinomas. Thus, iron(II) administered s.c. subsequent to DMBA initiation, greatly accelerated mammary carcinogenesis, implying its promoting activity for mammary tissue of female rats.      

Perfusión de extremidad aislada en Oncología

Resumen La perfusión de extremidad aislada (PEA) con melfalán es activa en el tratamiento de las metástasis en tránsito de melanoma, pero no ha mostrado eficacia en el de sarcomas de partes blandas irresecables de extremidad. Esta situación se ha visto modificada con la aparición del factor de necrosis tumoral-α (TNF), fármaco que destruye la vasculatura tumoral y aumenta de tres a 6 veces la captación selectiva de otros medicamentos por el tumor. Actualmente está demostrado que la PEA con TNF más melfalán es una modalidad terapéutica muy exitosa en ambas indicaciones para prevenir la amputación del miembro afecto. También hay datos contrastados sobre la eficacia de este régimen en tumores cutáneos multifocales y sarcomas óseos refractarios.      

Prediction of equilibrated postdialysis BUN by an artificial neural network in high-efficiency hemodialysis

In urea kinetic modeling, postdialysis blood urea nitrogen (BUN) is usually underestimated with an overestimation of the Kt/V especially in high-efficiency hemodialysis (HD). Thus, an artificial neural network (ANN) was used to predict the equilibrated BUN (Ceq) and equilibrated Kt/V (eKt/V60) by using both predialysis, postdialysis, and low-flow postdialysis BUN. The results were compared to a Smye formula to predict Ceq and a Daugirdas' formula (eKt/V30) to predict eKt/V60. Seventy-four patients on high-efficiency or high-flux HD were recruited. Their mean urea rebound was 28.6+/-2%. Patients were divided into a "training" set (n = 40) and a validation set (n = 34) for the ANN. Their status was exchanged later, and the two results were pooled. In the prediction of Ceq, both Smye formula and low-flow ANN were equally highly accurate. In patients with a high urea rebound (>30%), although Smye formula lost its accuracy, low-flow ANN remained accurate. In the prediction of eKt/V60, both Daugirdas' formula and low-flow ANN were equally accurate, although the Smye formula was not so accurate. In patients with a high urea rebound, although both Smye and Daugirdas' formulas lost their accuracy, low-flow ANN remained accurate. We concluded that low-flow ANN can accurately predict both Ceq and eKt/V60 regardless of the degree of urea rebound.     

Sleeping position and sudden infant death syndrome in Norway 1967-91

OBJECTIVE--To investigate, in a population based national study, the association between sleeping position of infants and the occurrence of sudden infant death syndrome (SIDS). DESIGN--A retrospective survey and registry based ecological study. A questionnaire based surveillance of sleeping position was obtained in a random sample (n = 34,799) and surveillance of SIDS was based on all infants born in Norway 1967-91, surviving the perinatal period. Variables studied from the questionnaire were usual sleeping position (placed), breast feeding at 3 months, and maternal smoking in pregnancy, and from the Medical Birth Registry maternal age, birth order, and birth weight. RESULTS--Proportion of infants sleeping prone increased from 1970 (7.4%) to 1989 (49.1%) and dropped in 1990 (26.8%) and 1991 (28.3%). Occurrence of SIDS increased from 1970 (1.1/1000) to 1989 (2.0) before dropping in 1990 and 1991 (1.1). IMPLICATION AND RELEVANCE OF RESULTS--A cause effect relationship between prone sleeping and SIDS as suggested in previous studies is supported by the present; and so far only, national study of infants' sleeping position.     

A case-control study of smoking and sudden infant death syndrome in the Scandinavian countries, 1992 to 1995. The Nordic Epidemiological SIDS Study

AIM: To establish whether smoking is an independent risk factor for sudden infant death syndrome (SIDS), if the effect is mainly due to prenatal or postnatal smoking, and the effect of smoking cessation. METHODS: The analyses were based on data from the Nordic epidemiological SIDS study, a case-control study with 244 cases and 869 controls. Odds ratios were computed by conditional logistic regression analysis. RESULTS: Smoking emerged as an independent risk factor for SIDS, and the effect was mainly mediated through maternal smoking in pregnancy (crude odds ratio 4.0 (95% confidence interval 2.9 to 5.6)). Maternal smoking showed a marked dose-response relation. There was no effect of paternal smoking if the mother did not smoke. Stopping or even reducing smoking was beneficial. SIDS cases exposed to tobacco smoke were breast fed for a shorter time than non-exposed cases, and feeding difficulties were also more common. CONCLUSIONS: Smoking is an independent risk factor for SIDS and is mainly mediated through maternal smoking during pregnancy. Stopping smoking or smoking less may be beneficial in reducing the risk of SIDS.     

Primary infections of Epstein-Barr virus, cytomegalovirus, and human herpesvirus-6

A total of 121 infants entered a cohort serological study of primary infections with herpes-viruses. All of them had seven samples of blood available: the first sample was taken soon after birth, the other six were taken at 1, 2, 3, 6, 12, and 14 months of age. One sample of maternal blood was collected immediately after delivery. All blood samples were tested for antibodies against cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 (HHV-6). Primary cytomegalovirus infection occurred early; the cumulative infection rates were 1.7%, 8.3%, 18.3%, 25%, 52.5%, and 65% by the ages of 1, 2, 3, 6, 12, and 14 months, respectively. Epstein-Barr virus infection was not seen before 3 months of age and slowly emerged thereafter, reaching a cumulative rate of 1.7%, 11.6%, 21.5% at the ages of 6, 12, and 14 months, respectively. Primary HHV-6 infection was also a rare event in the first three months of life, but peaked between 6 and 12 months of age. No detectable risk factors were associated with primary Epstein-Barr virus or HHV-6 infection. The risk factors associated with cytomegalovirus infection included breast feeding, fewer children in household, and care by a babysitter.