Evidence that small molecule enhancement of ß-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aß.

Certain mutant Alzheimer's amyloid-ß (Aß) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GAß). These mutant Aß peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing ß-hexosaminidase (ß-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aß aggregation and accumulation. The small molecule OT1001 is a ß-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ß-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric Aß as they age, as well as Aß oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain ß-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAß accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase ß-hex activity may be useful in reducing accumulation of certain mutant species of Aß and in preventing the associated behavioral pathology.

Immunomodulation and AD--down but not out.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the elderly. Interventions that remove existing fibrillar and oligomeric amyloid-ß (Aß) are believed to be essential for the success of any attempt at stabilization of brain function and mitigation of cognitive decline. Many of these strategies have focused on Aß vaccination and administration of anti-Aß antibodies. Both active and passive immunotherapies have been successful in mouse models, but both have had limited effect in clinical trials. Intravenous immunoglobulin (IVIG) has been proposed as a potential treatment for AD following evidence for behavioral benefit in AD models and cognitive benefit in early phase 1 and phase 2 clinical trials. A phase 3 trial IVIG trial failed to meet its primary outcomes. While there was a statistically significant benefit in moderate stage AD patients who carried an APOE ε4 allele, this stabilization of cognition was evident only on neuropsychological examination. No benefit on activities of daily living was evident, therefore failing to qualify AD as a new indication for IVIG. Identifying the biologically active component (s) responsible for the neuropsychological benefit in APOE ε4-positive AD patients could enable the development of a compound with greater potency that would qualify for FDA (US Food and Drug Administration) registration.

Carotenoids and retinoids: a review of research, clinical, and public health applications.

Traditionally, the carotenoids and retinoids have been regarded as dietary sources of vitamin A and have been evaluated regarding their respective physiologic roles in vision, growth, immune system integrity, and prevention of vitamin A deficiency. In the 1990s, however, vitamin A deficiency is no longer widespread in Western countries. Therefore, the role of carotenoids and retinoids is evolving to encompass treatment and prevention of conditions such as cancer and cardiovascular disease, which are prevalent in Western societies. This review summarizes current research concerning the therapeutic utility of vitamin A and its analogues and their roles in the prevention of cancer and cardiovascular disease.

Interpatient variability: genetic predisposition and other genetic factors.

Polymorphisms and other genetic factors related to enzymes metabolizing drugs and xenobiotic chemicals are well known. This article focuses on selected molecular mechanisms and introduces some of the clinical implications arising from genetically determined interpatient variability or expression in some of these enzymes. Selected are the polymorphic enzymes of cytochromes P-450 (CYP) as examples of phase I enzymes and methyl transferases, n-acetyl transferases, and glutathione-s-transferases as examples of phase II enzymes. The polymorphism surrounding arylhydrocarbon hydroxylase induction is briefly described. Phase I enzymatic reactions are predominantly oxidative, whereas phase II reactions often couple with the byproducts of phase I. Overall, in poor metabolizers, whether phase I or phase II, there is limited metabolism in most patients unless another major metabolic pathway involving other enzymes exists. Drug metabolism also depends on whether the parent compound is a prodrug that forms an active metabolite, and poor metabolizers under this condition will form only trace amounts of an active compound. Therefore, the clinical significance of genetic polymorphisms and other genetic factors may be related to substrate, metabolite, or the major elimination pathway.

C5b-7 and C5b-8 precursors of the membrane attack complex (C5b-9) are effective killers of E. coli J5 during serum incubation.

The finding that C9-deficient sera (C9D) can kill serum sensitive strains of Gram-negative bacteria by us and other investigators, questions the role of C9 in the membrane attack complex as necessary for cell death. In these studies we have demonstrated that C5b-8 complexes generated on E. coli J5 during incubation in C9-depleted and C9-neutralized sera are effective in killing Gram-negative bacteria. In the same study, we extended our investigations to show that the deposition of C5b-7 complexes (from C8-deficient [C8D], C8 depleted and C8-neutralized sera) is also effective in killing Gram-negative bacteria. In all cases, these studies demonstrated that when E. coli J5 was incubated with C8D, C9D and pooled normal human serum [PNHS], deposited C5b-9 complexes from PNHS produced more killing than C5b-7 or C5b-8 complexes alone. These experiments clearly demonstrated that C5b-7 and C5b-8 complexes are bactericidal and that multimeric C9 within C5b-9 is not an absolute requirement for inner membrane damage and cell death of Gram-negative bacteria.

The effect of caffeine on pregnancy outcome variables.

The American public consumes a wide array of caffeinated products as coffee, tea, chocolate, cola beverages, and caffeine-containing medication. Therefore, it seems of value to inform both the scientific community and the consumer about the potential effects of excessive caffeine consumption, particularly by pregnant women. The results of this literature review suggest that heavy caffeine use (> or = 300 mg per day) during pregnancy is associated with small reductions in infant birth weight that may be especially detrimental to premature or low-birth-weight infants. Some researchers also document an increased risk of spontaneous abortion associated with caffeine consumption prior to and during pregnancy. However, overwhelming evidence indicates that caffeine is not a human teratogen, and that caffeine appears to have no effect on preterm labor and delivery. More research is needed before unambiguous statements about the effects of caffeine on pregnancy outcome variables can be made.

Deoxyribonucleic acid, ribonucleic acid, and protein in the placentas of normal and selected complicated pregnancies.

Placenta from uncomplicated term pregnancies resulting in the birth of male infants weighing between 2900 and 3800 grams were analyzed for deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein content. The mothers of the infants all had pre-pregnancy weights within +/- 15 percent expected body weight for body frame, according to the Metropolitan Life Tables. There were no significant differences, as regards the content of DNA, RNA and protein, between the placental cotyledons. Nine placenta from mothers giving birth to growth retarded infants were analyzed along with the placenta from six mothers with insulin dependent diabetes mellitus. A trend suggesting less DNA in the placenta of the severely growth retarded (symmetric) infants when compared with placenta from the normal pregnancies was not noted in the less severely growth retarded (asymmetric) infants. The placenta from the infants of diabetic pregnancies contained DNA and RNA in amounts similar to that found in normal pregnancy placenta but the protein content was greater.

Prenatal predictors of performance on the Brazelton Neonatal Behavioral Assessment Scale.

The present study presents a prospective analysis of the interrelationships among prenatal medical, nutritional (dietary and biochemical) and behavioral determinants of Brazelton performance. Previous researchers (Scanlon 1984, Lester and Brazelton 1984) have raised questions regarding the relative roles of medical factors, nutrition, ponderal index and other behavioral factors in neonatal performance on the BNBAS. Four hundred sixty-seven predominantly Black nulliparous women and their neonates in Washington, D.C. who were enrolled in the study by the 20th week of gestation were subjects. Results of univariate tests of significant (P < 0.01) association between independent variables and Brazelton clusters from scores measured on day 2 are presented. The 26 behavioral items were summarized into 6 clusters as done in similar studies by linearizing measures made on a curvilinear scale and taking the mean. The 6 behavioral clusters are habituation, motor, orientation, range of states, regulation of states, and autonomic. Results of 16 reflex tests are used to define a seventh reflex cluster. Independent variables included demographic, lifestyle, nutritional, medical, ponderal index, and psychosocial measures. Several psychosocial variables, including stress, anxiety and partner interaction were associated with the behavioral clusters. Nutritional variables were associated with BNBAS habituation, motor, orientation, reflex score and autonomic responses. An analysis of co-variance was performed to determine the joint effect of the above variables on the variation in the Brazelton performance on the seven cluster scores. Five of the seven models (orientation, motor, range of states, autonomic, and reflex scores) were significant predictors of the outcome variables.

Maternal stress and pregnancy outcomes in a prenatal clinic population.

A two-fold decrease in the incidence of infant low birth weight, from 20.6% to 8.3%, occurred in Africa American women enrolled from 1985 to 1988 in this interdisciplinary research project conducted in an urban prenatal clinic. Nutritional, biochemical, medical, psychosocial, lifestyle, and environmental data were collected by trained Africa American interviewers. Several instruments were administered to the mother to specify the stress construct and assess body image, the social support network, and other psychosocial variables. The reduction in the incidence of low birth weight in an urban Africa American low income population admitted to the Howard University Hospital is attributed to the mediation of maternal stress by project personnel, in effect, providing an additional support system through the caring, sensitive environment provided by the project clinical staff, who met the women at each of their clinic-scheduled appointments. Women with a positive self attitude and higher self esteem were more likely to be delivered infants at term; the number of persons in the mother's social support network was directly correlated with her infant's gestational age. Maternal serum concentrations of the antioxidant vitamins, vitamin E and ascorbic acid, and the free radical scavenger, uric acid, were significantly correlated with serum folate and blood urea nitrogen. An hypothesis of low birth weight is presented.

Demographic profile, methodology, and biochemical correlates during the course of pregnancy.

This five-year prospective, observational study of urban women during their pregnancies was initiated in 1985 with the recruitment of women between the ages of 18 and 35 years in the prenatal clinics of Howard University Hospital and the District of Columbia Department of Human Services. The objective of the investigation was to characterize African American women by nutritional, biochemical, medical, sociocultural, psychological, lifestyle, and environmental parameters which could be used to formulate interventions to improve pregnancy outcomes. The women were all nulliparous, free of diabetes and abnormal hemoglobins, such as sickle cell disease, and no more than 28 weeks pregnant. During the early course of the study, it was apparent that 96% of the low income clinic patients had delivered infants of normal birth weight (> or = 2500 g), P = 0.001. Recruitment was then initiated at the District of Columbia General Hospital; women 16 and 17 years of age and at any gestational stage were included. This paper is the first in the series on African American women and their pregnancies. It will present the demographic characteristics of this regular cohort of 443 women who delivered live infants, the methodology used for biochemical, dietary, and psychosocial data sets, the mean values for infant gestational age, head circumference, body length, and birth weight from singleton births, and correlates of the mean values of biochemical variables for three trimesters of pregnancy with other biochemical parameters and those pregnancy outcomes.

Multiple factors as mediators of the reduced incidence of low birth weight in an urban clinic population.

A five year prospective observational study was initiated in 1985 at Howard University to describe the nutritional, clinical, dietary, lifestyle, environmental, and socioeconomic characteristics of women who enrolled in the hospital prenatal clinic. The participants were nulliparous, between the ages of 18 and 35 years, free of diabetes and abnormal hemoglobins (sickle cell disease, thalassemia, and hemoglobin C), and had been admitted prior to the 29th week of gestation. During the three year period from 1985-1988, the incidence of low birth weight (LBW) in 239 deliveries to project participants was 8.3%, whereas that of women simultaneously enrolled in the prenatal clinic with the same eligibility requirements, but not recruited for the research project, was 21.9% (P = 0.001). The incidence of LBW in infants of African American women with these eligibility requirements who were delivered by private physicians but were not enrolled in the project, was 6.3%. The reduction in LBW of infants delivered to participants in this study is attributed to the enhanced social and psychological support by project staff during their pregnancies. The caring, sensitive demeanor of the research project staff may have empowered the participants to (a) give greater compliance (91 vs. 70%) in the ingestion of the routine physician-prescribed vitamin/mineral supplement, which provided nutrients low (less than 70% of the 1989 RDAs) in their customary diets, such as folate, pyridoxine, iron, zinc, and magnesium and (b) show greater accountability in keeping prenatal clinic appointments.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary intakes, anthropometric measurements and pregnancy outcomes.

The relationships of maternal prenatal dietary intakes and anthropometric measurements to pregnancy outcomes were investigated in a prospective observational study of urban African American women. The 322 subjects, a subset of the 744 women recruited for the study using purposive sampling, were all nulliparous, free of diabetes mellitus and abnormal hemoglobins, and delivered term, singleton infants. Sociodemographic data and monthly quantitative 24-hour food recalls were collected by trained interviewers. Maternal anthropometric measurements were obtained from the subjects' hospital records. Pregnancy outcome data were obtained by physical examinations of the newborn infants by the project pediatrician. With the exception of vitamin C, average maternal dietary intakes were within the ranges of intakes obtained in previous studies. Mean intakes of protein, vitamins A and C, thiamin, riboflavin, and niacin exceeded the 1989 RDA, while those of food energy, vitamin B-6, folate, calcium, iron, magnesium, and zinc were below the RDA. Underweight prior to pregnancy and low pregnancy weight gains were found among 12.9% and 44.4% of the subjects respectively. Dietary intakes were not significantly correlated with pregnancy outcomes. Maternal anthropometric measurements significantly correlated with pregnancy outcomes included delivery weight, pregnancy weight gain, weekly weight gain, prepregnancy weight, net weight gain, height, prepregnancy body mass index, and % ideal prepregnancy body weight (P < 0.05). Using the stepwise selection procedure in multiple regression analysis, delivery weight, % ideal prepregnancy body weight, and prepregnancy body mass index were selected as being predictive of infant birth weight. It was concluded that anthropometric measurements were better nutritional predictors of pregnancy outcome than dietary intake.

Biochemical profile of African American women during three trimesters of pregnancy and at delivery.

The data presented are the results from a prospective observational study which was conducted to investigate the effects of nutrition and other related factors on the outcome of pregnancy in nulliparous African American women 16-35 years old. Fasting blood samples were collected from the women during the first, second and third trimesters of pregnancy. At delivery, both maternal and cord samples were collected. Biochemical variables such as, serum folate, vitamin B12, ascorbic acid, vitamin E, ferritin, selected minerals as well as complete blood count (CBC) and red cell folate were analyzed in the blood samples. The concentrations of hematocrit, hemoglobin, white blood cells, red blood cells and vitamin B12 were below the reference non-pregnant ranges throughout gestation. Maternal concentrations of folate and vitamin E increased sequentially with increased gestational age. Serum ferritin, during the third trimester, declined to 58% of the first trimester concentration. Maternal levels of ferritin at delivery were one third of the values found in the infant (cord) sample. Cord levels of folate, ascorbic acid and vitamin B12 were higher than the concentrations in the maternal delivery samples. The data suggest that among this group of pregnant women, major physiological changes, such as plasma volume expansion which alters blood chemistry and maternal to fetal transfer of nutrients, were similar to the findings of other investigators. In this population however, the findings for serum and whole blood folate are contrary to those reported by other researchers, and the sequential increase in the maternal concentration of the vitamin during pregnancy could be attributed to the use of vitamin supplements.

Pica in an urban environment.

The practice of pica, the compulsive ingestion of nonfood substances over a sustained period of time, was studied in 553 African American women who were admitted to prenatal clinics in Washington, D.C. Dietary, biochemical, and psychosocial correlates of the pica practices of a subset of this urban population are presented in this paper. Geophagia, compulsive eating of clay or dirt, was not observed in these women; pagophagia, or the ingestion of large quantities of ice and freezer frost, was self reported in 8.1% of the women, who consumed 1/2 to 2 cups a day from 1 to 7 days per week. Serum ferritin concentrations of pica women were significantly lower during the second and third trimesters of pregnancy; the average values for three trimesters of pregnancy for both ferritin and mean corpuscular hemoglobin were significantly lower in pica women than their nonpica counterparts (P = 0.0001 and P = 0.017, respectively). Although not significantly different, the iron (66 vs. 84% RDA) and calcium (60 vs. 75% RDA) contents of the diets of pica women were less those of nonpica women. Gestational age, body length, and body weight were not different, but head circumferences of infants delivered to pica women who consumed freezer frost and/or ice were smaller than those of nonpica women (P = 0.012). The hypothesis is presented that pica in African American women may be a mediator of stress, acting through the immune system. The size of the social support network of pica women was significantly less than that of nonpica women.(ABSTRACT TRUNCATED AT 250 WORDS)

Selected lifestyle practices in urban African American women--relationships to pregnancy outcome, dietary intakes and anthropometric measurements.

The relationships of selected lifestyle factors (cigarette smoking, consumption of alcoholic beverages, recreational drug use, and exercise during pregnancy), all self-reported, to pregnancy outcomes, dietary intake during pregnancy, and maternal anthropometric measurements, were investigated in a group of urban African American pregnant women. The 234 subjects were aged 16-35 years and were free of diabetes and abnormal hemoglobins. The lifestyle data were collected by trained interviewers during the subjects' prenatal clinic visits, and the dietary data by monthly, quantitative 24-hour food recalls conducted during these same visits. Maternal anthropometric measurements were obtained from the subjects' hospital records, and pregnancy outcome data during physical examinations of the newborn infants. Both cigarette smoking and drug use were associated with significantly lower mean birth weight, length, and head circumference, while exercise was associated with a significantly higher mean birth weight, and head circumference (P < 0.05). Drug use during pregnancy was associated with a significantly higher intake of vitamin C, and a significantly lower intake of iron; while women reporting drug use before pregnancy had significantly higher mean intakes of food energy, protein, total and saturated fat, and zinc. Prepregnancy weight, percent ideal prepregnancy body weight, prepregnancy body mass index, and delivery weight were significantly lower among those reporting drug use before pregnancy. Multiple regression analyses indicated that smoking explained a relatively small proportion of the variance in infant birth weight compared with delivery weight and percent of ideal prepregnancy body weight.

Relationships of serum illicit drug concentrations during pregnancy to maternal nutritional status.

Findings reported are for a subset of African American subjects, residing in the urban area of Washington, D. C., who participated in a Program Project designed to study nutrition, other factors, and the outcome of pregnancy. Fasting blood samples, drawn during each trimester of pregnancy and at delivery, were screened for concentrations of cocaine, phencyclidine (PCP) and marijuana. Since substance abusers are expected to consume inadequate diets, these samples were also analyzed for serum folate, vitamin B12, ferritin and ascorbic acid. Data for these biochemical variables were compared for subjects whose serum values for drugs were either above or below the drug screening threshold concentrations established by ADAMHA/NIDA. Pearson's correlations were used to determine relationships between pregnancy outcome variables and maternal serum drug concentrations. Blood samples drawn at delivery showed higher maternal: cord ratios (mean +/- SEM) for marijuana (3.3 +/- 2.2) and PCP (2.9 +/- 1.0) than for cocaine (1.0 +/- 0.2). The subjects whose serum values were above the ADAMHA/NIDA ranges for marijuana, PCP and cocaine had concentrations of folate and ferritin that were significantly less than those of subjects with lower serum drug levels (P < or = 0.05). High maternal serum concentrations of illicit drugs were accompanied by a significant increase in leukocyte count (P < or = 0.05). The level of maternal cocaine during the third trimester was inversely correlated with birthweight (r = -0.29; n = 52; P = 0.038) and head circumference (r = -0.28; n = 52; P = 0.047).(ABSTRACT TRUNCATED AT 250 WORDS)

Maternal low level lead and pregnancy outcomes.

We examined the relationship between the concentrations of blood lead and pregnancy outcomes in a subset of 349 African American women who enrolled in the program project, "Nutrition, Other Factors, and the Outcome of Pregnancy." Vitamin-mineral supplement users had significantly higher serum levels of ascorbic acid and vitamin E. Also, in supplement users, there were significantly lower mean concentrations of maternal blood lead. Inverse correlations were found between maternal levels of lead and the antioxidant vitamins, vitamin E and ascorbic acid. In addition, significant Pearson's correlations were observed between maternal blood lead levels and the following variables: positive correlations with calcium, phosphorus, mean corpuscular volume; inverse correlations with gestational age, Ponderal Index, infant orientation, and hematologic values. In the total subset, the three trimester sample means for maternal blood lead concentrations were not significantly different for mothers of infants who weighed less than 2500 g (low birth weight) and those who were delivered infants who weighed 2500 g or more. Clinically, nutrition may play a role in the reduction of potentially adverse effects from lead during pregnancy, i.e. protection of the fetus against lead toxicity and/or free radical damage through the antioxidant actions of vitamin E and ascorbic acid. Even when maternal blood lead levels are within the so-called "safe" range, maternal/use of a vitamin supplement supplying vitamin E and ascorbic acid during pregnancy may offer protection.

Nutrition, genital tract infection, hematologic values, and premature rupture of membranes among African American Women.

Using a prospective comparative design, African American gravidae with and without genital tract infection were assessed with respect to dietary intakes, serum nutrient values, hematologic values, and pregnancy outcomes. Intakes of ascorbic acid, vitamin A, protein, and iron were the dietary variables while levels of ascorbic acid, protein, albumin, globulin, and ferritin were the variables measured in serum. The hematologic variables included hemoglobin, hematocrit, and red and white blood cell counts. Pregnancy outcome was defined on the basis of premature rupture of the membranes (PROM), and infant birth weight, birth length, gestational age, and head circumference. The sample consisted of 335 nulliparous women who were between 16-35 years of age, 96 of whom had genital tract infection based on laboratory reports. Findings indicated no significant differences between the mean dietary intakes as well as serum values of the infected and non-infected women, and no difference in the incidence of PROM. However, non-infected women had a better mean hematologic profile than the infected gravidae during pregnancy. Also, for the non-infected group, there were significant relationships between head circumference and protein consumption (P = .015) and serum ferritin (P = .05). For the infected women, the relationship between the hemoglobin and hematocrit measurements obtained at the first prenatal visit and infant birth weight, birth length and head circumference were statistically significant.

Prenatal substance abuse and pregnancy outcomes among African American women.

Subjects in this prospective observational study were 467 nulliparous women, ages 16-35, recruited at the prenatal clinics of a university hospital and a public hospital. Using a purposive sampling approach, and entry questionnaire and a series of psychosocial instruments were administered throughout the pregnancy course to assess stress, anxiety, body image, self-esteem, pregnancy symptoms, locus of control, and partner's interaction. Several pregnancy outcome measures were determined after delivery. Brazelton neonatal behavioral assessments were performed two days after birth of infants delivered to the maternal subjects. Self-reported substance abuse data were obtained from the entry questionnaire and the medical intake records, with usage characterized in terms of occurrence prior to and/or during pregnancy. Illicit drug users during pregnancy had lower self-esteem, greater stress, more pregnancy symptoms, a more negative pre-pregnancy body image and less favorable interactions with their partners. T test results show that infants of smokers had smaller head circumferences, shorter body length, and less optimal Brazelton orientation performance. Infants of illicit drug users had smaller head circumferences and shorter body lengths.

The effects of aspirin-like drugs on the nutritional status of pregnant rats and offspring.

Previous studies have shown that salicylates and protein-calorie malnutrition independently compromise maturation and growth of infants. In the present study, pregnant rats were fed normal-and low-protein diets with and without aspirinlike drug treatments. The effects of a low-protein (8 percent) diet included decreases in total serum proteins in both dams and their offspring. Decreases in weight gains, serum albumin and globulin levels, and blood urea nitrogen (BUN) concentrations were detected in dams fed the low-protein diet without evidence of changes of these variables in their offspring.Salicylamide treatment was associated with decreased BUN values, and aspirin treatment was associated with decreased body-weight gains in both pregnant rats and offspring of dams fed the normal (25 percent) protein-control diet. Although aspirin treatment decreased weight gains, total serum protein and albumin levels, and BUN values, salicylamide decreased only the serum albumin levels of dams fed the normal-protein diet. Salicylamide treatment of dams fed the normal-protein diet was associated with decreased serum globulin levels, increased serum albumin-globulin ratios, and increased body-weight gains in their offspring.Both aspirin and salicylamide treatments were associated with decreased total serum protein levels in dams fed a low-protein diet. Aspirin treatment increased serum globulin levels and decreased serum albumin-globulin ratios in off-spring of dams fed the low-protein diet. The only effect of salicylamide treatment on offspring of dams fed the low-protein diet was decreased BUN values.It is concluded that aspirin treatment of pregnant rats was associated with more deleterious effects on their offspring than salicylamide treatment. Low maternal dietary protein conditions exacerbated effects associated with both salicylamide and aspirin treatments.