Long-term cerebrovascular dysfunction in the offspring from maternal electronic cigarette use during pregnancy.

Electronic cigarettes (E-cigs) have been promoted as harm-free or less risky than smoking, even for women during pregnancy. These claims are made largely on E-cig aerosol having fewer number of toxic chemicals compared with cigarette smoke. Given that even low levels of smoking are found to produce adverse birth outcomes, we sought to test the hypothesis that vaping during pregnancy (with or without nicotine) would not be harm-free and would result in vascular dysfunction that would be evident in offspring during adolescent and/or adult life. Pregnant female Sprague Dawley rats were exposed to E-cig aerosol (1 h/day, 5 days/wk, starting on gestational day 2 until pups were weaned) using e-liquid with 0 mg/mL (E-cig0) or 18 mg/mL nicotine (E-cig18) and compared with ambient air-exposed controls. Body mass at birth and at weaning were not different between groups. Assessment of middle cerebral artery (MCA) reactivity revealed a 51%-56% reduction in endothelial-dependent dilation response to acetylcholine (ACh) for both E-cig0 and E-cig18 in 1-mo, 3-mo (adolescent), and 7-mo-old (adult) offspring (P < 0.05 compared with air, all time points). MCA responses to sodium nitroprusside (SNP) and myogenic tone were not different across groups, suggesting that endothelial-independent responses were not altered. The MCA vasoconstrictor response (5-hydroxytryptamine, 5-HT) was also not different across treatment and age groups. These data demonstrate that maternal vaping during pregnancy is not harm-free and confers significant cerebrovascular health risk/dysfunction to offspring that persists into adult life. NEW & NOTEWORTHY These data established that vaping electronic cigarettes during pregnancy, with or without nicotine, is not safe and confers significant risk potential to the cerebrovascular health of offspring in early and adult life. A key finding is that vaping without nicotine does not protect offspring from cerebrovascular dysfunction and results in the same level of cerebrovascular dysfunction (compared with maternal vaping with nicotine), indicating that the physical and/or chemical properties from the base solution (other than nicotine) are responsible for the cerebrovascular dysfunction that we observed. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/maternal-vaping-impairs-vascular-function-in-theoffspring/.

The reliability and validity of a child and adolescent participation in decision-making questionnaire.

BACKGROUND: There is a growing impetus across the research, policy and practice communities for children and young people to participate in decisions that affect their lives. Furthermore, there is a dearth of general instruments that measure children and young people's views on their participation in decision-making. This paper presents the reliability and validity of the Child and Adolescent Participation in Decision-Making Questionnaire (CAP-DMQ) and specifically looks at a population of looked-after children, where a lack of participation in decision-making is an acute issue. METHODS: The participants were 151 looked after children and adolescents between 10-23 years of age who completed the 10 item CAP-DMQ. Of the participants 113 were in receipt of an advocacy service that had an aim of increasing participation in decision-making with the remaining participants not having received this service. RESULTS: The results showed that the CAP-DMQ had good reliability (Cronbach's alpha = 0.94) and showed promising uni-dimensional construct validity through an exploratory factor analysis. The items in the CAP-DMQ also demonstrated good content validity by overlapping with prominent models of child and adolescent participation (Lundy 2007) and decision-making (Halpern 2014). A regression analysis showed that age and gender were not significant predictors of CAP-DMQ scores but receipt of advocacy was a significant predictor of scores (effect size d = 0.88), thus showing appropriate discriminant criterion validity. CONCLUSION: Overall, the CAP-DMQ showed good reliability and validity. Therefore, the measure has excellent promise for theoretical investigation in the area of child and adolescent participation in decision-making and equally shows empirical promise for use as a measure in evaluating services, which have increasing the participation of children and adolescents in decision-making as an intended outcome.

The serotonin transporter 5-HTTPR polymorphism is associated with current and lifetime depression in persons with chronic psychotic disorders.

OBJECTIVE: Variation in the serotonin transporter gene (SLC6A4) promoter region has been shown to influence depression in persons who have been exposed to a number of stressful life events. METHOD: We evaluated whether genetic variation in 5-HTTLPR, influences current depression, lifetime history of depression and quantitative measures of depression in persons with chronic psychotic disorders. This is an association study of a genetic variant with quantitative and categorical definitions of depression conducted in the southwest US, Mexico and Costa Rica. We analyzed 260 subjects with a history of psychosis, from a sample of 129 families. RESULTS: We found that persons carrying at least one short allele had a statistically significant increased lifetime risk for depressive syndromes (P < 0.02, odds ratio 2.18, 95% CI 1.10-4.20). CONCLUSION: The 'ss' or 'sl' genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of psychotic individuals to develop major depression during the course of their illness.

Bioavailability of dexamethasone. II. Dexamethasone phosphate.

Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40-fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of 90%. The first-order rate constant for the conversion, 4.03 hr-1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best-fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg/ml.

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Aromatic amino acid hydroxylase inhibitors. 4. 3-Substituted alpha-methyltyrosines.

In the present study a series of 3-alkenyl-alpha-methyltyrosines and their corresponding 3-alkyl-and dihydrobenzofuran analogs was synthesized for potential tyrosine hydroxylase (TH) inhibitory activity. The appropriately substituted hydantoins IIIa and IIIb, which were prepared from the corresponding allyloxybenzylhydantoins IIa and IIb through Claisen rearrangement, served as intermediates for the synthesis of these amino acids. TH inhibition was reduced upon either saturation of the double bond in the side chain or cyclization to form the dihydrobenzofuran analogs. Formation of the epoxide had a similar effect. The inhibitory activity of these compounds against aromatic amino acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) was also investigated. Unsaturation, in both cases, decreases the inhibitory activity; however, the presence of a free phenolic group appears to be essential for AACD inhibitory activity.

Understanding of acquired immunodeficiency syndrome by elementary school children--a developmental survey.

OBJECTIVES: The developmental process by which young children acquire an understanding of the concepts of causality, treatment, and prevention of illness as related to acquired immunodeficiency syndrome (AIDS) is poorly understood. Previous studies have focused on adolescent populations and have measured the facts that children seem to know rather than their understanding of relevant concepts. Such approaches are likely to overestimate the child's true level of understanding and obscure significant misconceptions. The aims of this project are to measure directly the level of understanding of the concepts of causality, treatment, and prevention of AIDS in healthy, elementary school children and to assess the sociodemographic variables associated with their conceptual understanding. METHODS: Using a new, developmentally based, semistructured interview protocol (ASK, AIDS Survey for Kids), 361 children (57% black, 24% Hispanic, 19% white) in kindergarten through sixth grade at four public schools in New Haven, CT were interviewed. Responses to questions about causality, treatment, and prevention were scored for each of three illnesses (AIDS, and for comparison, colds and cancer) based on the level of conceptual sophistication of the response, irrespective of its factual accuracy. RESULTS: Scores for each of the concepts were highly intercorrelated and were correlated most strongly with grade level (R = .31 to .50, P < .0001 for each of these correlations, with the exception of the treatment of AIDS). Gender, race, and socioeconomic status did not contribute significantly to the variance observed for any of the concept scores in a linear regression model. Over-all, children's level of understanding of causality was significantly less sophisticated for AIDS than for colds (P < .0001); their level of conceptual understanding for the causality of AIDS was not significantly different from that of cancer (P = .9). CONCLUSIONS: Children's understanding of causality, treatment, and prevention of AIDS, as measured by the ASK, follows the same developmental sequence reported for children's understanding of general physical illness. Sociodemographic variables, such as race, gender, and socioeconomic status do not affect children's level of sophistication of these developmental concepts. These results have implications for the creation of developmentally appropriate and effective AIDS education curricula for primary and elementary grades. They also offer guidance to health care providers in their efforts to educate parents and young children about this important topic.

A randomized, controlled trial of a school-based, multi-faceted AIDS education program in the elementary grades: the impact on comprehension, knowledge and fears.

OBJECTIVE: Several educational theorists have suggested that young children are unlikely to benefit from detailed instruction regarding AIDS prevention because of inherent developmental cognitive limitations. This study aims to determine whether AIDS education in the elementary grades can advance young children's understanding of this illness. METHODS: A randomized, controlled trial was used to measure the impact of a 3-week, multifaceted AIDS education program on conceptual understanding, factual knowledge, and fears about AIDS in 189 students in grades kindergarten through 6th. The ASK (AIDS Survey for Kids), a standardized, semistructured interview that measures conceptual understanding, factual information, and fears about AIDS, was administered before and after the intervention. RESULTS: Children in the intervention group, as compared to those in the control group, showed significant (P < .0001) gains in their level of understanding of the concepts of causality and prevention of AIDS. These results were unaffected by controlling for grade, gender, race, socioeconomic status, and verbal fluency. The gains in children's understanding of causality of AIDS represented at least 2 years' growth in the level of conceptual sophistication and persisted at a follow-up evaluation several months later. After the intervention, more children (P < .001) in the intervention group than in the control group accurately identified causes of AIDS in response to open-ended questions: germ/germ theory (41% vs 13%), mother-to-infant transmission (54% vs 15%), blood transmission (83% vs 40%), and sexual transmission (56% vs 30%). Fewer than half as many children in the intervention group responded incorrectly to each of five direct questions about transmission of HIV through casual contact. The intervention did not increase children's fears about the illness. CONCLUSIONS: A short, developmentally based, multifaceted AIDS education program in the elementary grades can advance children's conceptual understanding and factual knowledge about AIDS and decrease their misconceptions about casual contact as a means of acquiring the illness, without increasing their fears. Significant advances in conceptual understanding about AIDS can be achieved through direct educational interventions.

Long-term therapy of hypertension with guanabenz.

Guanabenz, a centrally acting antihypertensive (alpha-agonist) that does not induce secondary sodium retention or other metabolic disturbances, was evaluated for up to two years at 19 investigational sites. In 329 patients completing six months of therapy, the mean supine diastolic blood pressure (SDBP) fell from 101 to 90 mmHg (P less than 0.01). Clinically significant individual SDBP decreases occurred in 74% of the patients by week 2, and these reductions were maintained in 72% at six months. Mean weight was reduced 1.4 lb (P less than 0.01), and mean supine pulse rate was decreased 5 beats/min (P less than 0.01). The most frequent effective doses were 8 and 16 mg BID (range, 2 to 32 mg BID). Principal side effects, usually mild, were sedation (31%), dry mouth (24%), dizziness (6%), and weakness (6%). Postural hypotension, impotence, and abrupt discontinuation symptoms were rare or absent. There were no clinically significant drug-related laboratory changes other than a 10 mg/100 ml mean serum cholesterol decrease. Two hundred twenty-two patients completed one year of therapy, and 80 completed two years, with little change in any parameters other than improvement in mean SDBP to 85 mmHg and in individual response rate to 84%. These results suggest that guanabenz is safe and effective for initial and sole therapy of hypertension.

Comparative antihypertensive effects of guanabenz and methyldopa.

The effects of guanabenz acetate, a centrally acting alpha-adrenergic, non-sodium-retaining antihypertensive agent, were compared with those of methyldopa in 248 hypertensive outpatients during a one-year, double-blind, multi-center study. Mean supine diastolic blood pressure (SDBP) decreased from 102 to 91 mmHg (P less than 0.01) among 78 guanabenz-treated patients and from 101 to 92 mmHg (P less than 0.01) among 89 methyldopa-treated patients who completed six months of treatment. Clinically significant individual SDBP decreases occurred in 76% of the guanabenz-treated patients and in 63% of the methyldopa-treated patients (P less thn 0.05). Blood pressure remained unchanged during the second six months, with response of 82% and 60%, respectively, for guanabenz and methyldopa (P less than 0.05). Although drowsiness and dry mouth occurred more frequently with guanabenz, evidence of fluid retention, such as weight gain, edema, and congestive heart failure, was significantly more frequent with methyldopa than with guanabenz. Because it does not induce volume expansion, guanabenz, unlike methyldopa, may be useful as sole initial antihypertensive therapy.

Liquid chromatographic determination including simultaneous "on-cartridge" separation of ranitidine cisapride drug combinations from paediatric plasma samples using an automated solid-phase extraction procedure.

HPLC methodology was investigated for the simultaneous determination of cisapride and ranitidine in small volume paediatric plasma samples. Such a simultaneous determination proved difficult due to the small sample volumes, the low concentrations of the drugs and the different log P values of the two compounds. The two drugs and their respective internal standards were separated "on-cartridge" using HLB Solid Phase Extraction cartridges and the samples quantified by individual HPLC methodologies. The technique has been applied successfully to 60 paediatric plasma samples containing both cisapride and ranitidine.

Children's understanding of the symptoms of AIDS.

Symptoms are the outward manifestations that allow children to identify and recognize illness; children's understanding of the symptoms of an illness may be directly related to their understanding of its cause or means of transmission. This study is the first empirical investigation of children's conceptual understanding and factual knowledge of the symptoms of AIDS. Children (N = 361; grades K to 6; 57% black, 24% Hispanic, 19% white; 52% female) attending four public schools in New Haven, Connecticut, were interviewed using a standardized semistructured interview (ASK, AIDS Survey for Kids) that included open-ended questions about the symptoms of AIDS and, for comparison, cancer and colds. Responses were scored for level of conceptual understanding and coded for factual content. For each illness, grade level was the variable most strongly correlated with symptomatology concept score (R = .42-.48, p < .0001) and contributed significantly (p < .0001) to the variance observed in concept score even after controlling for race, gender, verbal fluency, and socioeconomic status. The mean concept score was lower (p < .01) for symptomatology of AIDS (2.8 of possible 5) than for cancer (3.1) or colds (3.9). In addition, far more symptoms were named for colds than for either cancer or AIDS. Children who believed that HIV is spread via each of five potential means of transmission by casual contact were more likely (p < 01) to cite cold symptoms as symptoms of AIDS. We conclude that there exists a developmental progression in children's understanding of the symptomatology of AIDS. Children have a less sophisticated conceptual understanding and narrower factual knowledge base for AIDS than for colds and therefore have the capability to increase their understanding and knowledge about AIDS. Furthermore, improving children's understanding of the symptoms of AIDS may diminish misconceptions about transmission of HIV via casual contact.

Radioimmunoassay of indomethacin in biological fluids.

A radioimmunoassay was developed for the determination of indomethacin in biological fluids at concentrations as low as 50 ng/ml. Antibodies were produced in rabbits immunized with a conjugate of bovine serum albumin and indomethacin. This conjugate was prepared by an N-hydroxysuccinimide active ester procedure. Antiserums exhibited minimal cross-reactivity with the O-desmethyl and deschlorobenzoyl metabolites. However, the glucuronide conjugate was about three times as reactive as indomethacin, thus invalidating direct determinations of indomethacin in urine. This difficulty was circumvented by analyzing urine aliquots before and after conjugate hydrolysis. Concentrations of free and conjugated indomethacin were calculated by difference.

Analysis of sulindac and metabolites by combined isotope dilution-radioimmunoassay.

Sulindac, a new anti-inflammatory agent, and its sulfone and sulfide metabolites were conjugated to bovine serum albumin by the N-hydroxysuccinimide active ester procedure. Antiserum from rabbits immunized with each of these haptens exhibited extensive cross-reactivity, precluding differential analyses of the three species by displacement assay without prior separation. Therefore, an analytical method based on a combination of isotope dilution and radioimmunoassay was devised. A known mixture of the three chemical species, each labeled with tritium, was equilibrated with plasma or urine samples, reisolated chromatographically, and quantitated by binding to an appropriate immunoglobulin. The radiolabeled materials thus served as recovery standards as well as labeled antigens for each displacement assay. Sulindac and each of its metabolites in plasma or urine at concentrations as low as 500 ng/sample were differentially determined by this procedure. However, since an extraction is required, several milliliters of plasma can be used for each sample, thus increasing the actual sensitivity of the assay.

The use of hydrophilic lipophilic balanced (HLB) copolymer SPE cartridges for the extraction of diclofenac from small volume paediatric plasma samples.

The extraction of diclofenac from spiked aqueous and plasma samples by liquid-liquid extraction (LLE) and solid phase extraction (SPE) methods is compared. The SPE methodology utilised a hydrophilic lipophilic balanced (HLB) copolymer as the extraction phase. Using a literature HPLC method, a calibration curve for diclofenac was constructed in the range 1.0-50.0 microg/ml. Diclofenac spiked samples (aqueous and plasma) were extracted by LLE and SPE methodologies. The SPE resulted in higher extraction efficiencies (mean 94.9%) than the LLE (mean 78.9%) with %R.S.D.s similar in both methods (3.2 vs. 2.1%, respectively). The SPE method was suitable for the extraction of diclofenac from small volume paediatric plasma samples.

The use of polymeric solid phase extraction and HPLC analysis for the determination of ranitidine in routine plasma samples obtained from paediatric patients.

A sensitive HPLC method for the determination of ranitidine in small-volume (0.5 mL) paediatric plasma samples is described. Plasma samples were extracted using a simple, rapid solid phase extraction (SPE) technique developed using disposable copolymer packed SPE cartridges. Chromatographic separation was achieved by reverse-phase HPLC with isocratic elution using a microBondapak C18 column and a phosphate buffer (10 mM, pH 3.75)-acetonitrile (87:13 v/v) mobile phase with UV detection at 313 nm. The HPLC system exhibited linearity in the range 8-800 ng mL(-1). Intraday % CV and % bias values were in the range 1.28-8.09% (% bias -4.33 to -0.87) and interday % CV and % bias values were in the range 0.73-15.28% (% bias -1.80 to + 1.65). The limits of detection and quantitation obtained were 2 ng mL(-1) and 8 ng mL(-1), respectively, and ranitidine extraction recoveries from plasma ranged from 92.30 to 103.88%. In this study, the developed HPLC and SPE methodologies have been successfully applied to the determination of ranitidine concentrations in 68 paediatric plasma samples. The sampled population was drawn from patients already receiving the study drug therapeutically. Patients recruited had received ranitidine by two main routes - oral and intravenous. The plasma concentrations of ranitidine encountered in paediatric samples following oral or intravenous administration of a range of prescribed doses are presented graphically. These profiles are based on analysis of the first 68 plasma samples obtained from the first 35 patients recruited to the study receiving ranitidine by the oral or intravenous route.

Elementary school-age children's developmental understanding of the causes of cancer.

This study examines children's conceptual understanding and factual knowledge of the causes of cancer. Using a standardized, developmentally based, semistructured interview (ASK [AIDS (acquired immunodeficiency syndrome) Survey for Kids]), 784 children (43% black, 38% white, and 18% Hispanic; 48% female) in kindergarten through sixth grade attending six public elementary/middle schools in New Haven, Connecticut, were asked open-ended questions about the causes of cancer and, for comparison, the causes of colds and AIDS. Responses were scored for level of conceptual understanding and coded for factual content and factual accuracy. The level of conceptual understanding for causality of cancer increased consistently as grade level increased. When comparisons were made among the illnesses, children's level of conceptual understanding was significantly lower for the causes of cancer than for the causes of colds (p < .0001), but not significantly different from that of AIDS. Although the single most frequent cause of cancer mentioned was cigarettes/smoking (24%), more than one in five students stated that casual contact or contagion was a cause of cancer. More children cited causal contact/contagion than cited the following factually accurate or logically contributory causes combined: poor diet, air/water pollution or overexposure to sun, alcohol, and old age. Slightly more than one half of students in kindergarten through sixth grade worried about getting cancer, and the vast majority (80%) knew that cancer could be fatal. Children have a less sophisticated conceptual understanding of cancer than of colds and a very limited factual knowledge base for cancer, and thus they have the capacity to increase both their understanding and knowledge. These results have implications for the creation of developmentally appropriate cancer prevention curricula for elementary school-age children.

Cadmium accumulation and metallothionein synthesis in freshwater bivalves (Pyganodon grandis): relative influence of the metal exposure gradient versus limnological variability.

The relative influence of limnological confounding factors on cadmium (Cd) bioaccumulation and metallothionein (MT) synthesis was quantified in natural populations of freshwater bivalves (Pyganodon grandis) living in lakes along a Cd concentration gradient. During the ice-free period, we measured 15 environmental variables in the water compartment and determined total concentrations of Cd and MT in the gills of bivalves at 37 littoral stations in 20 lakes distributed across the mining area of Rouyn-Noranda in northwestern Quebec. A multiple linear regression model including pH (+), dissolved Ca concentrations (-) and free Cd2+ concentrations at the sediment-water interface (+) explained 74% of the variability in Cd concentrations in the bivalve gills. Dissolved Ca (-) and free Cd2+ (+) together explained 62% of the variation in MT concentrations in the bivalve gills. Partial linear regression analyses indicated that the limnological factors' pure and shared effects together accounted for 48 and 45% of the total variation in Cd and MT concentrations in the gills, respectively. A lake selection procedure that could be applied in monitoring programs is proposed to minimise the relative influence of these confounding variables.

Cadmium accumulation by invertebrates living at the sediment-water interface.

Benthic animals can take up trace metals both from the sediment compartment in which they burrow and from the water column compartment above their burrows (we define both compartments as containing water and particles). If criteria for the protection of benthic animals are based on metal concentrations in one of these two compartments, then it should first be demonstrated that the majority of the metal taken up by these animals comes from the given compartment. To determine whether benthic animals take up the majority of their cadmium (Cd) from the sediment compartment, we created a Cd gradient in lake sediment and compared Cd accumulation by the invertebrates colonizing these sediments with Cd concentrations in the sediment compartment. On the basis of this relationship and using a bioaccumulation model, we estimate that indigenous benthic invertebrates take up the majority of their Cd from the water column compartment. The results of our experiment are similar to those from a previous study conducted on a different benthic community in a larger lake. Taxa common to both lakes obtained similar proportions of their Cd from the water column compartment, suggesting that Cd accumulation by the same species will be constant across lakes of differing size and chemistry. Our results strengthen the argument that the protection of benthic communities from metal pollution should consider metal in both the water column and sediment compartments. In this regard, the AVS model, which considers only sedimentary metals, was more effective in predicting Cd concentrations in pore waters than those in most animal taxa. We suggest that measurements of vertical chemical heterogeneity in sediments and of animal behavior would aid in predicting the bioaccumulation and effects of sedimentary pollutants.

Non-conventional treatment of hepatic failures.

It is our intention to present a short review of various approaches to the non-conventional treatment of hepatic failures of the fulminant type. Our review is directed to the scientist, technologist, and clinician with a budding interest in the hepatic assist area. We shall discuss parabiosis, liver transplants, and various extracorporeal devices including hemoperfusion, hemodialysis, and enzymic detoxification systems. We feel that the present technological approaches to the treatment of hepatic failure are very primitive at this stage. Some of the recent advances are very encouraging, and it is our opinion that these approaches show great promise in the long term.