Pronounced Therapeutic Benefit of a Single Bidirectional AAV Vector Administered Systemically in Sandhoff Mice.

The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are fatal lysosomal storage disorders caused by mutations in the HEXA and HEXB genes, respectively. These mutations cause dysfunction of the lysosomal enzyme ß-N-acetylhexosaminidase A (HexA) and accumulation of GM2 ganglioside (GM2) with ensuing neurodegeneration, and death by 5 years of age. Until recently, the most successful therapy was achieved by intracranial co-delivery of monocistronic adeno-associated viral (AAV) vectors encoding Hex alpha and beta-subunits in animal models of SD. The blood-brain barrier crossing properties of AAV9 enables systemic gene therapy; however, the requirement of co-delivery of two monocistronic AAV vectors to overexpress the heterodimeric HexA protein has prevented the use of this approach. To address this need, we developed multiple AAV constructs encoding simultaneously HEXA and HEXB using AAV9 and AAV-PHP.B and tested their therapeutic efficacy in 4- to 6-week-old SD mice after systemic administration. Survival and biochemical outcomes revealed superiority of the AAV vector design using a bidirectional CBA promoter with equivalent dose-dependent outcomes for both capsids. AAV-treated mice performed normally in tests of motor function, CNS GM2 ganglioside levels were significantly reduced, and survival increased by >4-fold with some animals surviving past 2 years of age.

Volume and Infusion Rate Dynamics of Intraparenchymal Central Nervous System Infusion in a Large Animal Model.

Thalamic infusion of adeno-associated viral (AAV) vectors has been shown to have therapeutic effects in neuronopathic lysosomal storage diseases. Preclinical studies in sheep model of Tay-Sachs disease demonstrated that bilateral thalamic injections of AAV gene therapy are required for maximal benefit. Translation of thalamic injection to patients carries risks in that (1) it has never been done in humans, and (2) dosing scale-up based on brain weight from animals to humans requires injection of larger volumes. To increase the safety margin of this infusion, a flexible cannula was selected to enable simultaneous bilateral thalamic infusion in infants while monitoring by imaging and/or to enable awake infusions for injection of large volumes at low infusion rates. In this study, we tested various infusion volumes (200-800 µL) and rates (0.5-5 µL/min) to determine the maximum tolerated combination of injection parameters. Animals were followed for ∼1 month postinjection with magnetic resonance imaging (MRI) performed at 14 and 28 days. T1-weighted MRI was used to quantify thalamic damage followed by histopathological assessment of the brain. Trends in data show that infusion volumes of 800 µL (2 × the volume required in sheep based on thalamic size) resulted in larger lesions than lower volumes, where the long infusion times (between 13 and 26 h) could have contributed to the generation of larger lesions. The target volume (400 µL, projected to be sufficient to cover most of the sheep thalamus) created the smallest lesion size. Cannula placement alone did result in damage, but this is likely associated with an inherent limitation of its use in a small brain due to the length of the distal rigid portion and lack of stable fixation. An injection rate of 5 µL/min at a volume ∼1/3 of the thalamus (400-600 µL) appears to be well tolerated in sheep both clinically and histopathologically.

Neighborhood Deprivation Moderates Shared and Unique Environmental Influences on Hazardous Drinking: Findings from a Cross-Sectional Co-Twin Study.

Background: There has been increased interest in the interplay of genetic and environmental factors in the development of problematic alcohol use, including socioeconomic conditions of the neighborhood. Using a co-twin design, we examined the extent to which contributions of genetic, shared environmental, and unique environmental influences on hazardous drinking differed according to levels of neighborhood socioeconomic deprivation. Method: Data came from 1,521 monozygotic (MZ) and 609 dizygotic (DZ) twin pairs surveyed in Washington State. A measure of neighborhood deprivation was created based on census-tract-level variables and the Alcohol Use Disorders Identification Test 3-item instrument was used to assess level of hazardous drinking. We tested a series of nested structural equation models to examine associations among hazardous drinking, neighborhood deprivation, and the variance components (genetic [A], shared [C] and unique environmental [E] influences) of these two constructs, testing for both main effects and moderation by neighborhood deprivation. Results: Neighborhood deprivation was significantly associated with increased hazardous drinking, after accounting for A and C variance common to both phenotypes. Adjusting for within-pair differences in income and education, neighborhood deprivation moderated the magnitude of variance components of hazardous drinking, with the variance attributable to shared environment and non-shared environment increasing in more deprived neighborhoods. Conclusions: Findings point to amplification of early childhood as well as unique adulthood environmental risk on hazardous drinking in areas of greater deprivation.

Circadian clocks of both plants and pollinators influence flower seeking behavior of the pollinator hawkmoth Manduca sexta.

Most plant-pollinator interactions occur during specific periods during the day. To facilitate these interactions, many flowers are known to display their attractive qualities, such as scent emission and petal opening, in a daily rhythmic fashion. However, less is known about how the internal timing mechanisms (the circadian clocks) of plants and animals influence their daily interactions. We examine the role of the circadian clock in modulating the interaction between Petunia and one of its pollinators, the hawkmoth Manduca sexta. We find that desynchronization of the Petunia circadian clock affects moth visitation preference for Petunia flowers. Similarly, moths with circadian time aligned to plants show stronger flower-foraging activities than moths that lack this alignment. Moth locomotor activity is circadian clock-regulated, although it is also strongly repressed by light. Moths show a time-dependent burst increase in flight activity during subjective night. In addition, moth antennal responsiveness to the floral scent compounds exhibits a 24-hour rhythm in both continuous light and dark conditions. This study highlights the importance of the circadian clocks in both plants and animals as a crucial factor in initiating specialized plant-pollinator relationships.

Is marriage a buzzkill? A twin study of marital status and alcohol consumption.

Married adults have consistently been found to drink less than their single or divorced counterparts. This correlation may not be causal, however, as people nonrandomly "select" into marriage and into alcohol use. The current study uses a sample of 2,425 same-sex twin pairs (1,703 MZ; 722 DZ) to control for genetic and shared environmental selection, thereby eliminating a great many third variable, alternative explanations to the hypothesis that marriage causes less drinking. Married twins were compared with their single, divorced, and cohabiting cotwins on drinking frequency and quantity. Married cotwins consumed fewer alcoholic beverages than their single or divorced cotwins, and drank less frequently than their single cotwins. Alcohol use patterns did not differ among married and cohabiting twins. These findings provide strong evidence that intimate relationships cause a decline in alcohol consumption. (PsycINFO Database Record

Socioeconomic modifiers of genetic and environmental influences on body mass index in adult twins.

OBJECTIVE: Individual measures of socioeconomic status (SES) suppress genetic variance in body mass index (BMI). Our objective was to examine the influence of both individual-level (i.e., educational attainment, household income) and macrolevel (i.e., neighborhood socioeconomic advantage) SES indicators on genetic contributions to BMI. METHOD: The study used education level data from 4,162 monozygotic (MZ) and 1,900 dizygotic (DZ) same-sex twin pairs (64% female), income level data from 3,498 MZ and 1,534 DZ pairs (65% female), and neighborhood-level socioeconomic deprivation data from 2,327 MZ and 948 DZ pairs (65% female). Covariates included age (M = 40.4 ± 17.5 years), sex, and ethnicity. The cotwin control model was used to evaluate the mechanisms through which SES influences BMI (e.g., through genetic vs. environmental pathways), and a gene-by-environment interaction model was used to test whether residual variance in BMI, after controlling for the main effects of SES, was moderated by socioeconomic measures. RESULTS: SES significantly predicted BMI. The association was noncausal, however, and instead was driven primarily through a common underlying genetic background that tended to grow less influential as SES increased. After controlling for the main effect of SES, both genetic and nonshared environmental variance decreased with increasing SES. CONCLUSIONS: The impact of individual and macrolevel SES on BMI extends beyond its main effects. The influence of genes on BMI is moderated by individual and macrolevel measures of SES, such that when SES is higher, genetic factors become less influential.

Sleep Duration and Area-Level Deprivation in Twins.

STUDY OBJECTIVES: We used quantitative genetic models to assess whether area-level deprivation as indicated by the Singh Index predicts shorter sleep duration and modifies its underlying genetic and environmental contributions. METHODS: Participants were 4,218 adult twin pairs (2,377 monozygotic and 1,841 dizygotic) from the University of Washington Twin Registry. Participants self-reported habitual sleep duration. The Singh Index was determined by linking geocoding addresses to 17 indicators at the census-tract level using data from Census of Washington State and Census Tract Cartographic Boundary Files from 2000 and 2010. Data were analyzed using univariate and bivariate genetic decomposition and quantitative genetic interaction models that assessed A (additive genetics), C (common environment), and E (unique environment) main effects of the Singh Index on sleep duration and allowed the magnitude of residual ACE variance components in sleep duration to vary with the Index. RESULTS: The sample had a mean age of 38.2 y (standard deviation [SD] = 18), and was predominantly female (62%) and Caucasian (91%). Mean sleep duration was 7.38 h (SD = 1.20) and the mean Singh Index score was 0.00 (SD = 0.89). The heritability of sleep duration was 39% and the Singh Index was 12%. The uncontrolled phenotypic regression of sleep duration on the Singh Index showed a significant negative relationship between area-level deprivation and sleep length (b = -0.080, P < 0.001). Every 1 SD in Singh Index was associated with a ∼4.5 min change in sleep duration. For the quasi-causal bivariate model, there was a significant main effect of E (b(0E) = -0.063; standard error [SE] = 0.30; P < 0.05). Residual variance components unique to sleep duration were significant for both A (b(0Au) = 0.734; SE = 0.020; P < 0.001) and E (b(0Eu) = 0.934; SE = 0.013; P < 0.001). CONCLUSIONS: Area-level deprivation has a quasi-causal association with sleep duration, with greater deprivation being related to shorter sleep. As area-level deprivation increases, unique genetic and nonshared environmental residual variance in sleep duration increases.

Behavioral and Environmental Modification of the Genetic Influence on Body Mass Index: A Twin Study.

Body mass index (BMI) has a strong genetic basis, with a heritability around 0.75, but is also influenced by numerous behavioral and environmental factors. Aspects of the built environment (e.g., environmental walkability) are hypothesized to influence obesity by directly affecting BMI, by facilitating or inhibiting behaviors such as physical activity that are related to BMI, or by suppressing genetic tendencies toward higher BMI. The present study investigated relative influences of physical activity and walkability on variance in BMI using 5079 same-sex adult twin pairs (70 % monozygotic, 65 % female). High activity and walkability levels independently suppressed genetic variance in BMI. Estimating their effects simultaneously, however, suggested that the walkability effect was mediated by activity. The suppressive effect of activity on variance in BMI was present even with a tendency for low-BMI individuals to select into environments that require higher activity levels. Overall, our results point to community- or macro-level interventions that facilitate individual-level behaviors as a plausible approach to addressing the obesity epidemic among US adults.

Psychological distress, emotional stability, and emotion regulation moderate dynamics of herpes simplex virus type 2 recurrence.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) genital lesion recurrence is modulated by psychological factors, but no such link with viral shedding (and thus asymptomatic transmission) has been observed in humans. PURPOSE: The moderating effects of average psychological distress, emotional stability, and emotion regulation on HSV-2 recurrence were tested. METHODS: Nineteen HSV-2 seropositive women were followed over 22 weeks. Daily measures of HSV-2 recurrence and psychological distress were collected. HSV-2 lesions and viral shedding were modeled as linear oscillator systems, with psychological distress moderating the periodicity of each process. RESULTS: High levels of distress, more labile moods, and less ability to regulate emotional states were associated with fewer days elapsed between the onset of lesion episodes. Viral shedding showed the same pattern. CONCLUSIONS: Results are consistent with research indicating that psychological distress suppresses immune system functioning, and provide new evidence that genital HSV-2 viral shedding is related to, and regulated by, psychological distress.

Quasi-causal associations of physical activity and neighborhood walkability with body mass index: a twin study.

OBJECTIVE: Physical activity, neighborhood walkability, and body mass index (BMI, kg/m(2)) associations were tested using quasi-experimental twin methods. We hypothesized that physical activity and walkability were independently associated with BMI within twin pairs, controlling for genetic and environmental background shared between them. METHODS: Data were from 6376 (64% female; 58% identical) same-sex pairs, University of Washington Twin Registry, 2008-2013. Neighborhood walking, moderate-to-vigorous physical activity (MVPA), and BMI were self-reported. Residential address was used to calculate walkability. Phenotypic (non-genetically informed) and biometric (genetically informed) regression was employed, controlling for age, sex, and race. RESULTS: Walking and MVPA were associated with BMI in phenotypic analyses; associations were attenuated but significant in biometric analyses (Ps<0.05). Walkability was not associated with BMI, however, was associated with walking (but not MVPA) in both phenotypic and biometric analyses (Ps<0.05), with no attenuation accounting for shared genetic and environmental background. CONCLUSIONS: The association between activity and BMI is largely due to shared genetic and environmental factors, but a significant causal relationship remains accounting for shared background. Although walkability is not associated with BMI, it is associated with neighborhood walking (but not MVPA) accounting for shared background, suggesting a causal relationship between them.

Do maladaptive behaviors exist at one or both ends of personality traits?

In the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; American Psychiatric Association, 2013) personality disorder trait model, maladaptive behavior is located at one end of continuous scales. Widiger and colleagues, however, have argued that maladaptive behavior exists at both ends of trait continua. We propose that the role of evaluative variance differentiates these two perspectives and that once evaluation is isolated, maladaptive behaviors emerge at both ends of nonevaluative trait dimensions. In Study 1, we argue that evaluative variance is worthwhile to measure separately from descriptive content because it clusters items by valence regardless of content (e.g., lazy and workaholic; apathetic and anxious; gullible and paranoid; timid and hostile, etc.), which is unlikely to describe a consistent behavioral style. We isolate evaluation statistically (Study 2) and at the time of measurement (Study 3) to show that factors unrelated to valence evidence maladaptive behavior at both ends. We argue that nonevaluative factors, which display maladaptive behavior at both ends of continua, may better approximate ways in which individuals actually behave.

A phenotypic null hypothesis for the genetics of personality.

We review the genetically informed literature on the genetics of personality. Over the past century, quantitative genetic studies, using identical and fraternal twins, have demonstrated that differences in human personality are substantially heritable. We focus on more contemporary questions to which that basic observation has led. We examine whether differences in the heritability of personality are replicable across different traits, samples, and studies; how the heritability of personality relates to its reliability; and how behavior genetics can be employed in studies of validity, and we discuss the stability of personality in genetic and environmental variance. The appropriate null hypothesis in behavior genetics is not that genetic or environmental influence on personality is zero. Instead, we offer a phenotypic null hypothesis, which states that genetic variance is not an independent mechanism of individual differences in personality but rather a reflection of processes that are best conceptualized at the phenotypic level.

Accounting for the physical and mental health benefits of entry into marriage: a genetically informed study of selection and causation.

Married adults show better psychological adjustment and physical health than their separated/divorced or never-married counterparts. However, this apparent "marriage benefit" may be due to social selection, social causation, or both processes. Genetically informed research designs offer critical advantages for helping to disentangle selection from causation by controlling for measured and unmeasured genetic and shared environmental selection. Using young-adult twin and sibling pairs from the National Longitudinal Study of Adolescent Health (Harris, 2009), we conducted genetically informed analyses of the association between entry into marriage, cohabitation, or singlehood and multiple indices of psychological and physical health. The relation between physical health and marriage was completely explained by nonrandom selection. For internalizing behaviors, selection did not fully explain the benefits of marriage or cohabitation relative to being single, whereas for externalizing symptoms, marriage predicted benefits over cohabitation. The genetically informed approach provides perhaps the strongest nonexperimental evidence that these observed effects are causal.

Eliminating routine oral contrast use for CT in the emergency department: impact on patient throughput and diagnosis.

This study aimed to assess the effect of eliminating routine oral contrast use for abdominopelvic (AP) computed tomography (CT) on emergency department (ED) patient throughput and diagnosis. Retrospective analysis was performed on patients undergoing AP CT during 2-month periods prior to and following oral contrast protocol change in an urban, tertiary care ED. Patients with inflammatory bowel disease, prior gastrointestinal tract-altering surgery, or lean body habitus continued to receive oral contrast. Oral contrast was otherwise eliminated from the AP CT protocol. Patients were excluded if they would not have typically received oral contrast, regardless of the intervention. Data recorded include patient demographics, ED length of stay (LOS), time from order to CT, 72-h ED return, and repeat imaging. Two thousand and one ED patients (1,014 before and 987 after protocol change) underwent AP CT during the study period. Six hundred seven pre-intervention and 611 post-intervention were eligible for oral contrast and included. Of these, 95 % received oral contrast prior to the intervention and 42 % thereafter. After the intervention, mean ED LOS among oral contrast eligible patients decreased by 97 min, P < 0.001. Mean time from order to CT decreased by 66 min, P < 0.001. No patient with CT negative for acute findings had additional subsequent AP imaging within 72 h at our institution that led to a change in diagnosis. Eliminating routine oral contrast use for AP CT in the ED may be successful in decreasing LOS and time from order to CT without demonstrated compromise in acute patient diagnosis.

Anterior versus lateral needle decompression of tension pneumothorax: comparison by computed tomography chest wall measurement.

OBJECTIVES: Recent research describes failed needle decompression in the anterior position. It has been hypothesized that a lateral approach may be more successful. The aim of this study was to identify the optimal site for needle decompression. METHODS: A retrospective study was conducted of emergency department (ED) patients who underwent computed tomography (CT) of the chest as part of their evaluation for blunt trauma. A convenience sample of 159 patients was formed by reviewing consecutive scans of eligible patients. Six measurements from the skin surface to the pleural surface were made for each patient: anterior second intercostal space, lateral fourth intercostal space, and lateral fifth intercostal space on the left and right sides. RESULTS: The distance from skin to pleura at the anterior second intercostal space averaged 46.3 mm on the right and 45.2 mm on the left. The distance at the midaxillary line in the fourth intercostal space was 63.7 mm on the right and 62.1 mm on the left. In the fifth intercostal space the distance was 53.8 mm on the right and 52.9 mm on the left. The distance of the anterior approach was statistically less when compared to both intercostal spaces (p < 0.01). CONCLUSIONS: With commonly available angiocatheters, the lateral approach is less likely to be successful than the anterior approach. The anterior approach may fail in many patients as well. Longer angiocatheters may increase the chances of decompression, but would also carry a higher risk of damage to surrounding vital structures.

Revisiting the effect of marital support on depressive symptoms in mothers and fathers: a genetically informed study.

This article uses a genetically informed design to evaluate whether (1) the well-documented association between marital support and depressive symptoms is accounted for by genetic and/or shared environmental selection, (2) gender differences are found after controlling for selection effects, and (3) parenthood moderates any nonshared environmental relation between depressive symptoms and marital support. We used a sample of 1,566 pairs of same-sexed, married twins from the Australian Twin Registry to evaluate our hypotheses that (1) the predicted effect of marital support on depressive symptoms is not fully an artifact of selection, (2) the etiological sources accounting for this effect differ between husbands and wives, and (3) parenthood status moderates the effect of marital support on depressive symptoms adjusting for selection effects. The results support the first hypotheses. However, after controlling for selection, the effect of marital support on depressive symptoms was not significantly different for husbands and wives. Parenthood moderated the effect of marital support, such that after controlling for selection, marital support is more strongly associated with depressive symptoms for full-time parents than nonfull-time parents.

Aflatoxins in ginseng roots.

Ginseng roots can be infected by molds during growth, harvest and storage and result in contamination with mycotoxins. In this study, an analytical method for the determination of aflatoxins B(1), B(2), G(1) and G(2), a group of structurally similar mycotoxins, in ginseng root was developed. Test samples were extracted with methanol-water (8?+?2), diluted and passed through an immunoaffinity column packed with antibodies specific for aflatoxins. The purified extract was then derivatized with a mixture of water, trifluoroacetic acid and acetic acid. Aflatoxins were then separated and quantified by reverse phase liquid chromatography (LC) with fluorescence detection. Recoveries of total aflatoxins at 2, 4, 8 and 16 ng/g added to toxin-free 4 to 5-year old dried sliced Wisconsin ginseng were 92, 77, 91 and 83% respectively; and relative standard deviations were 3.6, 8.0, 6.9 and 2.0% respectively. A total of 11 wild simulated and 12 cultivated ginseng root samples were analysed for aflatoxins. All cultivated roots were found to be free of aflatoxin contamination. Two of the wild simulated roots contained total aflatoxins B(1), B(2), G(1) and G(2) at 15.1 and 15.2 ng/g. One moldy ginseng root purchased from a grocery store was found to be contaminated with aflatoxins at 16 ng/g.