Social impairments in Rett syndrome: characteristics and relationship with clinical severity.

BACKGROUND: While behavioural abnormalities are fundamental features of Rett syndrome (RTT), few studies have examined the RTT behavioural phenotype. Most of these reports have focused on autistic features, linked to the early regressive phase of the disorder, and few studies have applied standardised behavioural measures. We used a battery of standardised measures of behaviour and functioning to test the following hypotheses: (1) autistic behaviour is prominent throughout childhood in RTT; (2) autistic features are more salient in individuals with milder presentation; (3) severity of autistic behaviour is associated with a wider range of behavioural problems; and (4) specific MECP2 mutations are linked to more severe autistic behaviour. METHODS: Eighty MECP2 mutation-positive girls with RTT (aged 1.6-14.9 years) were administered: (1) the Screen for Social Interaction (SSI), a measure of autistic behaviour suited for individuals with severe communication and motor impairment; (2) the Rett Syndrome Behaviour Questionnaire (RSBQ), covering a wide range of abnormal behaviours in RTT; (3) the Vineland Adaptive Behavior Scales (VABS); and (4) a modified version of the Rett Syndrome Severity Scale (RSSS). Regression analyses examined the predictive value of age and RSSS on autistic behaviour and other behavioural abnormalities. T-tests further characterised the behavioural phenotype of individual MECP2 mutations. RESULTS: While age had no significant effect on SSI or RSBQ total scores in RTT, VABS Socialization and Composite scores decreased over time. Clinical severity (i.e. RSSS) also increased with age. Surprisingly, SSI performance was not related to either RSSS or VABS Composite scores. Autistic behaviour was weakly linked with the RSBQ Hand behaviour factor scores, but not with the RSBQ Fear/Anxiety factor. Clinical (neurological) severity did not predict RSBQ scores, as evidenced by the analysis of individual MECP2 mutations (e.g. p.R106W, p.R270X and p.R294X). CONCLUSIONS: Our data suggest that in RTT, autistic behaviour persists after the period of regression. It also demonstrated that neurological and behavioural impairments, including autistic features, are relatively independent of one another. Consistent with previous reports of the RTT phenotype, individual MECP2 mutations demonstrate complex associations with autistic features. Evidence of persistent autistic behaviour throughout childhood, and of a link between hand function and social skills, has important implications not only for research on the RTT behavioural phenotype, but also for the clinical management of the disorder.

Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats.

Exposure to environmentally relevant levels of lead (Pb(2+)) during early life produces deficits in hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and spatial learning in young adult rats [Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233-242; Guilarte TR, Toscano CD, McGlothan JL, Weaver SA (2003) Environmental enrichment reverses cognitive and molecular deficits induced by developmental lead exposure. Ann Neurol 53:50-56]. Other evidence suggests that the performance of rats in the Morris water maze spatial learning tasks is associated with the level of granule cell neurogenesis in the dentate gyrus (DG) [Drapeau E, Mayo W, Aurousseau C, Le Moal M, Piazza P-V, Abrous DN (2003) Spatial memory performance of aged rats in the water maze predicts level of hippocampal neurogenesis. Proc Natl Acad Sci U S A 100:14385-14390]. In this study, we examined whether continuous exposure to environmentally relevant levels of Pb(2+) during early life altered granule cell neurogenesis and morphology in the rat hippocampus. Control and Pb(2+)-exposed rats received bromodeoxyuridine (BrdU) injections (100 mg/kg; i.p.) for five consecutive days starting at postnatal day 45 and were killed either 1 day or 4 weeks after the last injection. The total number of newborn cells in the DG of Pb(2+)-exposed rats was significantly decreased (13%; P<0.001) 1 day after BrdU injections relative to controls. Further, the survival of newborn cells in Pb(2+)-exposed rats was significantly decreased by 22.7% (P<0.001) relative to control animals. Co-localization of BrdU with neuronal or astrocytic markers did not reveal a significant effect of Pb(2+) exposure on cellular fate. In Pb(2+)-exposed rats, immature granule cells immunolabeled with doublecortin (DCX) displayed aberrant dendritic morphology. That is, the overall length-density of the DCX-positive apical dendrites in the outer portion of the DG molecular layer was significantly reduced up to 36% in the suprapyramidal blade only. We also found that the area of Timm's-positive staining representative of the mossy fibers terminal fields in the CA3 stratum oriens (SO) was reduced by 26% in Pb(2+)-exposed rats. These findings demonstrate that exposure to environmentally relevant levels of Pb(2+) during early life alters granule cell neurogenesis and morphology in the rat hippocampus. They provide a cellular and morphological basis for the deficits in synaptic plasticity and spatial learning documented in Pb(2+)-exposed animals.

Ethane: a marker of lipid peroxidation during cardiopulmonary bypass in humans.

The goals of this study were to (1) determine the utility of quantification of ethane as a marker of ischemia-reperfusion during human cardiopulmonary bypass (CPB); and (2) determine, using an animal model for this surgical procedure, whether the mode of surgical approach produced increases the quantity of exhaled ethane. Human CPB was initiated following standard anesthetic and monitoring regimens. Samples of gas were collected at baseline and at multiple defined time points throughout the studies. Ethane was determined using cryogenic concentration and gas chromatography. Sternotomy increased exhaled ethane compared to baseline (p < .007; 5.8 +/- 1.7 vs. 3.0 +/- 0.7 nmol/m2 x min); ethane returned to baseline levels prior to the initiation of CPB. Aortic unclamping produced ethane elevation (p < .05; 2.3 +/- 0.8 vs. 1.5 +/- 0.4 nmol/m2 x min) with the levels being related to a lower cardiac index and a higher systemic vascular resistance post aortic unclamping. Termination of CPB significantly increased ethane levels compared to baseline (p < .002; 4.8 +/- 1.7 vs. 3.0 +/- 0.7 nmol/m2 x min). Independent variables that correlated with increased ethane measurements included a higher arterial blood pH on bypass and the change in hemoglobin pre- and post-CPB. Electrocautery, but not scalpel, incision of the porcine abdominal wall increased ethane levels significantly (p < .02). These results indicate that exhaled ethane may be a valuable marker of lipid peroxidation during and following CPB.

Naltrexone alters subjective and psychomotor responses to alcohol in heavy drinking subjects.

Preclinical studies support endogenous opioid system involvement in alcohol reinforcement and consumption; however, recent clinical trials and human laboratory studies have provided mixed findings of the effects of naltrexone (a non-selective opioid antagonist) on alcohol responses. This study used a within-subject design (n = 23) to investigate naltrexone effects (0, 50 and 100 mg qd) on subjective and psychomotor responses to alcohol (none, moderate, high) in heavy drinkers. Before alcohol administration, subjects reported decreased desire to drink alcohol when maintained on 50 mg compared with placebo naltrexone. Following alcohol administration, active naltrexone significantly increased subjective ratings of sedative, and unpleasant/sick effects and decreased ratings of liking, best effects and desire to drink. Naltrexone generally did not alter subjective or objective indicators of drunkenness. Finally, high doses of naltrexone and alcohol interacted to produce the greatest decreases in liking and best effects. Findings support the role of endogenous opioids as determinants of alcohol's effects and suggest that naltrexone may be particularly clinically useful in those treatment patients who continue to drink heavily.

Naltrexone dampens ethanol-induced cardiovascular and hypothalamic- pituitary-adrenal axis activation.

Alcohol ingestion activates the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. This study examined naltrexone effects on alcohol-induced increases in physiological responses and their association with alcohol liking. Using a within-subjects design, heavy drinking men (N = 19) were maintained on each of three naltrexone doses (0, 50, and 100 mg, p.o.) over an 8-day inpatient stay. Within each naltrexone dose, subjects had three alcohol challenge sessions (none, moderate, high) in random order. Autonomic, subjective and endocrine measurements were collected regularly prior to and following alcohol administration. High-dose alcohol ingestion increased heart rate, diastolic blood pressure, skin temperature, ACTH, cortisol and liking of drink effects; responses following the moderate alcohol dose were less consistent. Naltrexone significantly dampened alcohol-induced increases in heart rate, diastolic blood pressure, hormone levels and subjective liking of drink effects. This dampening of cardiovascular and hormonal responses may contribute to the therapeutic effectiveness of naltrexone for reducing alcohol liking and decreasing relapse in alcohol-dependent persons.

Genetic ascertainment with heterogeneous risk.

Analysis of the bias of ascertainment is reformulated to deal with more general patterns commonly encountered in practice. The goal is to provide a unifying theory that will both replace the traditional, rather piecemeal, treatment of the problem and free it from certain restrictive assumptions. A compact algebraic method is furnished for analyzing the properties of the distributions by means of the probability generating function (PGF). The scope of the generalization is illustrated by applying it to the various classical patterns of bias of ascertainment. It is extended to other patterns in which the conditions of ascertainment, though more plausible, are also logically more complicated. It also accommodates cases hitherto inadequately dealt with, such as where the segregation ratios are heterogeneous (for example because of age-dependence); and cases where the ascertainment function is of arbitrary form and denies us such valuable, but demanding, assumptions as independence. Not only is the result unifying, but it leads to usable results in specific application such as diseases that depend on age or birth order. While the commonest applications are in human genetics, there are many other issues (such as the use of batteries of tests) in which it is equally important.

The bingo model of survivorship: 1. probabilistic aspects.

A "bingo" model is one in which the pattern of survival of a system is determined by whichever of several components, each with its own particular distribution for survival, fails first. The model is motivated by the study of lifespan in animals. A number of properties of such systems are discussed in general. They include the use of a special criterion of skewness that probably corresponds more closely than traditional measures to what the eye observes in casually inspecting data. This criterion is the ratio, r(h), of the probability density at a point an arbitrary distance, h, above the mode to that an equal distance below the mode. If this ratio is positive for all positive arguments, the distribution is considered positively asymmetrical and conversely. Details of the bingo model are worked out for several types of base distributions: the rectangular, the triangular, the logistic, and by numerical methods, the normal, lognormal, and gamma.

Infra-red laser ablative micromachining of parylene-C on SiO2 substrates for rapid prototyping, high yield, human neuronal cell patterning.

Cell patterning commonly employs photolithographic methods for the micro fabrication of structures on silicon chips. These require expensive photo-mask development and complex photolithographic processing. Laser based patterning of cells has been studied in vitro and laser ablation of polymers is an active area of research promising high aspect ratios. This paper disseminates how 800 nm femtosecond infrared (IR) laser radiation can be successfully used to perform laser ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes (derived from the human teratocarcinoma cell line (hNT)) whilst 248 nm nanosecond ultra-violet laser radiation produces photo-oxidization of the parylene-C and destroys cell patterning. In this work, we report the laser ablation methods used and the ablation characteristics of parylene-C for IR pulse fluences. Results follow that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells. We disseminate the variation in yield of patterned hNT astrocytes on parylene-C with laser pulse spacing, pulse number, pulse fluence and parylene-C strip width. The findings demonstrate how laser ablative micromachining of parylene-C on SiO2 substrates can offer an accessible alternative for rapid prototyping, high yield cell patterning with broad application to multi-electrode arrays, cellular micro-arrays and microfluidics.

Low cost, patterning of human hNT brain cells on parylene-C with UV & IR laser machining.

This paper describes the use of 800nm femtosecond infrared (IR) and 248nm nanosecond ultraviolet (UV) laser radiation in performing ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes. Results are presented that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells while UV laser radiation produces photo-oxidation of the parylene-C and destroys cell patterning. The findings demonstrate how IR laser ablative micromachining of parylene-C on SiO2 substrates can offer a low cost, accessible alternative for rapid prototyping, high yield cell patterning.

Coherent light scattering from semicontinuous silver nanoshells near the percolation threshold.

We report on measurements of visible extinction spectra of semicontinuous silver nanoshells grown on colloidal silica spheres. We find that thin, fractal shells below the percolation threshold exhibit geometrically tunable plasmon resonances. A modified scaling theory approach is used to model the dielectric response of such shells, which is then utilized to obtain the extinction cross section in a retarded Mie scattering formalism. We show that such spherical resonators support unique plasmon dynamics: in the visible there is a new regime of coherently driven cluster-localized plasmons, while crossover to homogeneous response in the infrared predicts a delocalized shell plasmon.

Composite sampling.

In sampling certain types of materials, such as bags of fertilizer, or subsampling large quantities of water, as might be done in investigating the density of plankton in certain environmental situations, it is customary to composite the samples. That is, several samples are drawn, mixed into a composite sample, and a sample taken from the composite is then used to determine relevant characteristics of the population. In this paper the results of Brown and Fisher [1972] are extended to more complex situations (e.g., more than one variance component present).

The longer-term effectiveness of residential lead paint abatement.

Residential lead-based paint and settled dust are important sources of lead exposure in U.S. children. Scant information exists on the long-term effectiveness of alternative lead abatement practices. In this extended (1.5-3.5 years) follow-up study of comprehensive abatement, 179 wipe dust samples were collected in 13 occupied dwellings for which pre- and immediately postabatement (clearance) dust lead data were available. Dust lead loadings (mg/m2) 1.5 to 3.5 years postabatement were 16, 10, and 4% of preabatement levels for floors, window sills, and window wells, respectively. Furthermore, 78% of readings remained within Maryland's interim clearance standards, indicating that sustained reductions of dust lead hazards were achieved in comprehensively abated dwellings located in older unabated housing areas.

Dynamics of platelet-activating-factor release and uptake in a human neutrophil suspension.

The present study has examined the dynamics of platelet-activating-factor (PAF) synthesis, release and uptake in order to understand better the trafficking of PAF between cells and medium. Initial experiments indicated that the amount of PAF found on the outside of the cell remained constant well after the synthesis from a precursor had apparently stopped, and in spite of a continued capacity of the cell to take up and catabolize PAF. These results suggested that PAF produced and stored within the cell is eventually released to the outside of the cell at a rate proportional to that of cellular uptake. In order to estimate the amount of PAF released from the cell, the processes of PAF release and uptake were modelled using simple mathematical functions. It was found that, under the experimental conditions used in this study, the uptake of PAF could be expressed as an exponential function tending to a non-zero baseline. Utilizing this rate constant for the uptake of PAF with the amount of PAF outside the cell, the amount of total PAF released from the cell was estimated. Data from the model suggested PAF was released in amounts 10-fold higher than could actually be measured over 30 min. In fact, the model predicted more PAF could be released from the cell than is synthesized, suggesting that a portion of the PAF which is released is taken up and then released again to the outside of the cell. The potential for PAF and/or its intermediates to be recycled was verified by demonstrating that a large proportion of exogenously provided 1-alkyl-2-lyso-sn-glycero-3-phosphocholine is taken up by the neutrophil, converted into PAF and then released again by the cell. These results suggest that PAF trafficking between the cell and medium is complex and involves many processes, which include synthesis, release, uptake, catabolism and recycling.

Influence of serum cholesterol and albumin on partitioning of PCB congeners between human serum and adipose tissue.

The influence of serum lipids and proteins on partitioning of individual polychlorinated biphenyl (PCB) congener peaks between human serum and adipose tissue lipid was assessed using regression analysis. Subjects were 55 repair workers who were either currently or previously exposed, and 56 comparison workers without occupational exposure to PCBs. Seven congeners (2,4,5,4'-tetra CB, 2,3,5,2',3',6'-hexa CB, 2,3,4,2',3',6'-hexa CB, 2,3,4,2',4',5'-hexa CB, 3,4,5,3',4'-penta CB, 2,3,4,5,2',3',4'-hepta CB, and 2,3,4,5,2',3',4',5'-octa CB) which had been quantified in both serum and adipose tissue in at least one-third of the total study population were selected for evaluation. Initially the crude correlations between the serum PCB and certain candidate variables were assessed; more than one congener was correlated with serum cholesterol, albumin, triglycerides, low-density lipoproteins, very low-density lipoproteins, age, body fat content, and average servings of fish per day. Stepwise regression of log serum congener concentration on log adipose congener concentration and these variables was performed. Only cholesterol, albumin, and average servings of fish per day were significant for at least one congener peak. Congeners behaved in two groups, depending on their order of chromatographic elution. For 2,4,5,4'-tetra CB, 2,3,5,2',3',6'-hexa CB, and 2,3,4,2',3',6'-hexa CB, log serum concentration was not significantly correlated with log adipose congener concentration, and there was no consistent pattern for significant candidate variables. For congeners 2,3,4,2',4',5'-hexa CB, 3,4,5,3',4'-penta CB, 2,3,4,5,2',3',4'-hepta CB, and 2,3,4,5,2',3',4',5'-octa CB, log serum congener concentration was consistently significantly correlated with log adipose congener concentration and serum cholesterol positively, and with serum albumin negatively. For these four congeners the explanations of variation (R2) in serum congener concentration using adipose congener concentration alone were 3, 23, 20, and 30%, respectively, and after adding cholesterol and albumin were 13, 56, 43, and 46%. Thus we conclude that serum cholesterol and albumin can influence the distribution or partition of PCBs between serum and adipose tissue.

Hereditary polyposis coli. III. Genetic and evolutionary fitness.

The numbers of progeny born to 355 patients with heritable polyposis of the colon and to 315 related, but normal, subjects, all old enough to have completed their families, are presented, as well as data on 432 subjects still young enough to have more children. Two main indices are used: mean family size ("genetic fitness") and the complement of the extinction probability of the line ("evolutionary fitness"), both of which suppose a steady state. Point- and interval-estimates (the latter derived by an extension of Stigler's method) are furnished. It is estimated that the probability a new mutant gene will persist is one in four for Gardner syndrome, one in 20 for familial polyposis coli, and 0 for Peutz-Jeghers syndrome. There is evidence of bimodality in family size, suggesting voluntary infertility in a proportion of subjects. The data confirm our provisional working assumption that most families are completed by the time women are in their mid-40's and men in their mid-50's.

Medical economics survey-methods study: cost-effectiveness of alternative survey strategies.

The Medical Economics Survey-Methods Study was conducted under contract for the National Center for Health Statistics during 1975-76. The objective was to determine the cost-effectiveness of a variety of strategies under consideration for application in a national survey in 1977. Detailed data on health care utilization and expenditures were collected periodically from a panel of 691 Maryland households over a seven-month period. Issues tested through a random experimental design included the relative effectiveness of monthly versus bimonthly interviews and in-person versus telephone contact. Completeness and accuracy of information were determined through an extensive record check involving all providers and third party payers identified in the household check involving all providers and third party payers identified in the household survey. The results indicate that there are substantial deficiencies in the household reporting and that the household data for all types of medical services would benefit from the availability of record data in order to improve theri accuracy. The frequency of contact (monthly versus bimonthly) had little effect on the accuracy of reporting. Given the higher rate of attrition observed for the monthly procedures and their considerably greater cost, the bimonthly interval appears to offer advantages. In-person contact resulted in significantly better reporting compared with telephone contact in the Baltimore area, but no difference was found in more rural Washington County. Thus, the 10 per cent cost increase for in-person contact may well be justified by the improved accuracy of the data obtained for certain types of populations.

Soil lead abatement and children's blood lead levels in an urban setting.

OBJECTIVES: The effect of abating soil lead was assessed among Baltimore children. The hypothesis was that a reduction of 1000 parts per million would reduce children's blood lead levels by 0.14 to 0.29 mumol/L (3-6 micrograms/dL). METHODS: In 2 neighborhoods (study and control), 187 children completed the protocol. In the study area, contaminated soil was replaced with clean soil. RESULTS: Soil lead abatement in this study did not lower children's blood lead. CONCLUSIONS: Although it did not show an effect in this study, soil lead abatement may be useful in certain areas.

Comparison of a wipe and a vacuum collection method for the determination of lead in residential dusts.

Lead-containing house dust is an important source of childhood lead exposure. Standard methods for collection of settled dust for evaluation of lead content have not been established. Little is known about the relationships between the various wipe and vacuum-based methods employed in past studies, preventing meaningful comparisons of results. This study characterized the relationship between a frequently used wipe dust collection method and a vacuum-based in-line filter method used to collect dust in a national survey of lead in paint and dust in U.S. housing. The correlation coefficient was 0.82 for estimates of lead loadings (PbD, mg/m2) from 71 pairs of side-by-side wipe and vacuum dust samples collected from uncarpeted floors, window sills, and exterior window wells in six dwellings. Geometric mean (GM) wipe PbD estimates exceeded those for vacuum samples by a factor of 3.9 and 5.7 for floors and window sills, respectively, findings consistent with the multiple sources of sample loss associated with the vacuum sampler. For window wells, the GM vacuum PbD estimate exceeded the GM wipe PbD estimate by a factor of 3.4, possibly due to the use of an alternative vacuum nozzle. The resulting increase in the estimated prevalence of U.S. homes with elevated dust lead loadings had wipe-sampling instead of vacuum-sampling methods been used in the national survey is discussed.

Evaluation of Hawaii's Healthy Start Program.

Hawaii's Healthy Start Program (HSP) is designed to prevent child abuse and neglect and to promote child health and development in newborns of families at risk for poor child outcomes. The program operates statewide in Hawaii and has inspired national and international adaptations, including Healthy Families America. This article describes HSP, its ongoing evaluation study, and evaluation findings at the end of two of a planned three years of family program participation and follow-up. After two years of service provision to families, HSP was successful in linking families with pediatric medical care, improving maternal parenting efficacy, decreasing maternal parenting stress, promoting the use of nonviolent discipline, and decreasing injuries resulting from partner violence in the home. No overall positive program impact emerged after two years of service in terms of the adequacy of well-child health care; maternal life skills, mental health, social support, or substance use; child development; the child's home learning environment or parent-child interaction; pediatric health care use for illness or injury; or child maltreatment (according to maternal reports and child protective services reports). However, there were agency-specific positive program effects on several outcomes, including parent-child interaction, child development, maternal confidence in adult relationships, and partner violence. Significant differences were found in program implementation between the three administering agencies included in the evaluation. These differences had implications for family participation and involvement levels and, possibly, for outcomes achieved. The authors conclude that home visiting programs and evaluations should monitor program implementation for faithfulness to the program model, and should employ comparison groups to determine program impact.