Anatomical pulmonary magnetic resonance imaging segmentation for regional structure-function measurements of asthma.

PURPOSE: Pulmonary magnetic-resonance-imaging (MRI) and x-ray computed-tomography have provided strong evidence of spatially and temporally persistent lung structure-function abnormalities in asthmatics. This has generated a shift in their understanding of lung disease and supports the use of imaging biomarkers as intermediate endpoints of asthma severity and control. In particular, pulmonary (1)H MRI can be used to provide quantitative lung structure-function measurements longitudinally and in response to treatment. However, to translate such biomarkers of asthma, robust methods are required to segment the lung from pulmonary (1)H MRI. Therefore, their objective was to develop a pulmonary (1)H MRI segmentation algorithm to provide regional measurements with the precision and speed required to support clinical studies. METHODS: The authors developed a method to segment the left and right lung from (1)H MRI acquired in 20 asthmatics including five well-controlled and 15 severe poorly controlled participants who provided written informed consent to a study protocol approved by Health Canada. Same-day spirometry and plethysmography measurements of lung function and volume were acquired as well as (1)H MRI using a whole-body radiofrequency coil and fast spoiled gradient-recalled echo sequence at a fixed lung volume (functional residual capacity + 1 l). We incorporated the left-to-right lung volume proportion prior based on the Potts model and derived a volume-proportion preserved Potts model, which was approximated through convex relaxation and further represented by a dual volume-proportion preserved max-flow model. The max-flow model led to a linear problem with convex and linear equality constraints that implicitly encoded the proportion prior. To implement the algorithm, (1)H MRI was resampled into ∼3 × 3 × 3 mm(3) isotropic voxel space. Two observers placed seeds on each lung and on the background of 20 pulmonary (1)H MR images in a randomized dataset, on five occasions, five consecutive days in a row. Segmentation accuracy was evaluated using the Dice-similarity-coefficient (DSC) of the segmented thoracic cavity with comparison to five-rounds of manual segmentation by an expert observer. The authors also evaluated the root-mean-squared-error (RMSE) of the Euclidean distance between lung surfaces, the absolute, and percent volume error. Reproducibility was measured using the coefficient of variation (CoV) and intraclass correlation coefficient (ICC) for two observers who repeated segmentation measurements five-times. RESULTS: For five well-controlled asthmatics, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) was 83% ± 7% and FEV1 was 86 ± 9%pred. For 15 severe, poorly controlled asthmatics, FEV1/FV C = 66% ± 17% and FEV1 = 72 ± 27%pred. The DSC for algorithm and manual segmentation was 91% ± 3%, 92% ± 2% and 91% ± 2% for the left, right, and whole lung, respectively. RMSE was 4.0 ± 1.0 mm for each of the left, right, and whole lung. The absolute (percent) volume errors were 0.1 l (∼6%) for each of right and left lung and ∼0.2 l (∼6%) for whole lung. Intra- and inter-CoV (ICC) were <0.5% (>0.91%) for DSC and <4.5% (>0.93%) for RMSE. While segmentation required 10 s including ∼6 s for user interaction, the smallest detectable difference was 0.24 l for algorithm measurements which was similar to manual measurements. CONCLUSIONS: This lung segmentation approach provided the necessary and sufficient precision and accuracy required for research and clinical studies.

Young men's intimate partner violence and relationship functioning: long-term outcomes associated with suicide attempt and aggression in adolescence.

BACKGROUND: Longitudinal research supports that suicidal thoughts and behaviors in adolescence predict maladjustment in young adulthood. Prior research supports links between suicide attempt and aggression, perhaps because of a propensity for impulsive behavior in states of high negative affect that underlies both problems. Such vulnerability may increase risk for intimate partner violence and generally poor young adulthood relational adjustment. METHOD: A total of 153 men participated in annual assessments from ages 10-32 years and with a romantic partner at three assessments from ages 18-25 years. Multi-method/multi-informant constructs were formed for parent/family risk factors, adolescent psychopathology (e.g. suicide-attempt history, mother-, father-, teacher- and self-reported physical aggression) and young adulthood relational distress (jealousy and low relationship satisfaction) and maladaptive relationship behavior (observed, self- and partner-reported physical and psychological aggression toward a partner, partner-reported injury, official domestic violence arrest records and relationship instability). RESULTS: Across informants, adolescent aggression was correlated with suicide-attempt history. With few exceptions, aggression and a suicide attempt in adolescence each predicted negative romantic relationship outcomes after controlling for measured confounds. Adolescent aggression predicted young adulthood aggression toward a partner, in part, via relationship dissatisfaction. CONCLUSIONS: Boys' aggression and suicide-attempt history in adolescence each predict poor relationship outcomes, including partner violence, in young adulthood. Findings are consistent with the theory of a trait-like vulnerability, such as impulsive aggression, that undermines adaptation across multiple domains in adolescence and young adulthood. Prevention and intervention approaches can target common causes of diverse public health problems.

Introduction to special section on three-generation studies.

Interest in lifespan research and cross-generational associations in parenting practices and child behaviors has grown rapidly in recent years. The four papers presented in this journal test three key intergenerational research questions regarding intergenerational continuities for externalizing behaviors, using different 3-generational samples.

Physical aggression in a community sample of at-risk young couples: gender comparisons for high frequency, injury, and fear.

The associations of frequent physical aggression, injury, and fear were examined for a community-based sample of at-risk young couples who were dating, cohabiting, or married. It was hypothesized that frequent physical aggression toward a partner, in the range of shelter samples, is largely caused by antisocial behavior and mutual couple conflict and, thus, that there would be greater similarity across genders in such behavior than has previously been supposed. It was also predicted that levels of injury and fear would be higher in women but that some men would experience these impacts. Findings indicated similarity across genders both in the prevalence of frequent aggression and in its association with antisocial behavior. Furthermore, such aggression was likely to be bidirectional in couples. Contrary to the hypothesis of the study, rates of injury and fear for the women were not significantly higher than for the men.

Aggression toward female partners by at-risk young men: the contribution of male adolescent friendships.

Deviancy training was examined as a risk factor for physical and psychological aggression toward a female partner among boys and young men in the Oregon Youth Study. Hostile talk about women during videotaped male friendship interactions was hypothesized to indicate a process by which aggression toward women is reinforced within male peer networks. Both antisocial behavior and hostile talk were predicted to be associated with later aggression toward a female partner. Prospective developmental models were tested from 9-10 years of age through young adulthood. Findings indicated that the relation of deviant peer association in adolescence and later aggression toward a partner was mediated by antisocial behavior; observed hostile talk about women with male peers explained additional variance in aggression toward a partner.

Intergenerational transmission of abuse: a two-generational prospective study of an at-risk sample.

OBJECTIVE: A model was examined in which the association between a parent's history of abuse and the parent's own abusive behavior toward his or her children was hypothesized to be mediated by parental psychopathology, early childbearing, and consistency of discipline. Additionally, the effect of severity of abuse on the likelihood of becoming abusive was examined. METHOD: Participants were 109 parents (G1) and their male children (G2) who were involved in a longitudinal study. The G1 parents reported on their own experiences of abuse when they were children. Ten years later, the G2 youths reported on the G1 parents' abusive behavior toward them. A number of other factors, including parental socioeconomic status (SES), antisocial behavior, depression and Post-traumatic Stress Disorder (PTSD), consistency of discipline, and the perceived early difficulty of the G2 children were measured. RESULTS: As reported by their own children, parents who reported having been abused in childhood were significantly more likely to engage in abusive behaviors toward the next generation. Findings indicated that abuse experienced by the parents, as well as consistency of discipline and depression plus PTSD, were predictive of parental abuse of the child. Contrary to hypotheses, the effects were not fully mediated. However, there were significant interactions between parental history of abuse and consistency of discipline, as well as abuse history and depression and PTSD. Parents who had experienced multiple acts of abuse and at least one physical impact were more likely to become abusive than were the other parents. CONCLUSIONS: The implications of these findings for preventive interventions are discussed.

Highly efficient solid phase synthesis of oligonucleotide analogs containing phosphorodithioate linkages.

A triester method for the synthesis of deoxynucleoside phosphorodithioate dimers is described. The phosphorodithioate linkage is introduced using a new dithiophosphorylating reagent DPSE-SP(S)Cl(2)where DPSE = 2-diphenylmethylsilylethyl. This group is removed quickly using tetra-butylammonium fluoride leading to the quantitative formation of phosphorodithioate diesters uncontaminated with the corresponding phosphorothioates. The utility of this group is demonstrated by the synthesis of a penta-decathymidylic acid, [T(PS(2))T(PO(2))](7)T, which contains alternating phosphorodithioate/phosphate diester internucleotide linkages.

Adolescent and family predictors of physical aggression, communication, and satisfaction in young adult couples: a prospective analysis.

This study tested a model wherein the family conflict, depression, and antisocial behavior of 254 adolescents (mean age = 17 years; 63% female) are prospectively related to functioning within a marital (51%) or dating relationship in young adulthood (mean age = 23 years). Family aversive communication in adolescence and adolescent antisocial behavior predicted couple physical aggression. Family aversive communication predicted dyadic satisfaction and aversive couple communication for married women and dating men. Among those with partners who reported little antisocial behavior, adolescent antisocial behavior inversely predicted couple satisfaction and facilitative behavior. Partner antisocial behavior did not mediate the relation between adolescent characteristics and couple functioning. Findings emphasize the importance of the early family environment and psychopathology of the adolescent in the development of adaptive couple relationships.

Co-occurrence of conduct problems and depressive symptoms in early adolescent boys: III. Prediction to young-adult adjustment.

The prediction of young-adult adjustment from early adolescent conduct problems and depressive symptoms was examined for an at-risk sample of approximately 200 males. Conduct problems and depressive symptoms were expected to show stability to young adulthood. It was predicted that early adolescent conduct problems would be associated with a broad range of adjustment problems in young adulthood due to cumulative adjustment failures. Early adolescent depressive symptoms were expected particularly to predict poor relationships with parents and peers. Additive and interactive effects of the two predictors were examined. Conduct problems and depressive symptoms showed significant stability to young adulthood. Conduct problems were associated with a broad range of adjustment problems including continuing problems in peer associations, substance use, self-esteem, relationships with parents, and new problems in noncompletion of education, unemployment, driver's license suspensions, and causing pregnancies. Depressive symptoms predicted particularly to problems in social relationships. Higher levels of both conduct problems and depressive symptoms in early adolescence did not predict to increased difficulties for any one outcome over either problem alone, either due to main or interaction effects. Such co-occurrence, however, did result in problem outcomes in multiple areas, thus, the poorest adjustment overall.

Prospective family predictors of aggression toward female partners for at-risk young men.

Social learning models of the intergenerational transmission of aggression were tested for an at-risk sample of young adult men who entered a longitudinal study (Oregon Youth Study) in Grade 4 and were assessed with a female partner in young adulthood (17-20 years old). The associations of 2 family process variables--parental dyadic aggression and unskilled parenting, assessed both in late childhood and early adolescence with the son's later aggression toward a partner--were examined. Parental antisocial behavior was hypothesized to be associated with both family process variables. Unskilled parenting was hypothesized to play a key role in the son's later aggression toward an intimate partner, mediated by his development of antisocial behavior by adolescence. Fully prospective structural equation models were tested with multimethod, multiagent data, including both observed and reported aggression toward the partner. Findings indicate that the major hypothesized pathways through unskilled parenting practices and the boys' antisocial behavior were implicated in the intergenerational transmission of aggression.

Becoming an adolescent father: precursors and parenting.

Precursors and outcomes of adolescent pregnancy receive considerable research attention; however, most studies deal with adolescent mothers. This study examined whether risk factors that are precursors to adolescent fatherhood would be consistent with the family coercion model (G. R. Patterson, 1976) of the development of antisocial behavior in childhood. Hypotheses were tested in the Oregon Youth Study (OYS) sample of 206 at-risk boys who were first seen at 9 or 10 years of age. At 18-20 years of age, the profiles for the 35 adolescent fathers included more arrests and substance use than the other OYS participants. At around 2 years of age, 40% of the children had no contact with their fathers. The children, compared with a normative control sample, had somewhat greater health risks. The at-risk parents, compared with a control sample, were observed to show higher levels of negative reactions when their children were working on a puzzle task.

Conducting ecologically valid prevention research: recruiting and retaining a "whole village" in multimethod, multiagent studies.

Many prevention studies are now designed with complementary interventions in different settings. Evaluations of these interventions require assessing the child's behavior in each of these settings. Conducting these studies, therefore, may involve recruiting school districts, principals, classroom teachers, peers, parents, siblings, and in later years, employers and intimate partners. These participants may be considered natural raters or satellite subjects, depending on their degree of involvement. Issues of recruitment and retention thus are magnified in multimethod, multiagent studies. To illustrate these issues, findings are presented for three studies conducted with risk populations in the past decade at the Oregon Social Learning Center: a passive longitudinal study, a selected prevention study, and an indicated prevention study. Findings indicate that achieving high recruitment and retention rates for at-risk and high-risk subjects in multisetting studies is possible, and that a developmental approach should be taken to recruiting risk populations.

A 27-kDa matrix receptor from rat brain synaptosomes: selective recognition of the Arg-Gly-Asp-Ser domain and unique resistance to calcium-dependent proteolysis.

A 27-kDa protein from adult rat brain synaptosomes was purified by matrix-affinity chromatography. The matrix receptor interacted with the Arg-Gly-Asp-Ser sequence recognized by integrin-type adhesion molecules, and was labeled by integrin antibodies. Levels of the 27-kDa species in brain membranes were unaffected by proteolysis, however, conventional integrin subunits exhibited robust degradation. This unique resistance to proteolysis may allow the new matrix receptor to contribute to the stability of synaptic contacts.

Recognition of GC base pairs by triplex forming oligonucleotides containing nucleosides derived from 2-aminopyridine.

We have attempted to alleviate the pH dependency of triplex recognition of guanine by using intermolecular triplexes containing 2-amino-5-(2-deoxy-d-ribofuranosyl)pyridine (AP) as an analogue of 2'-deoxycytidine (dC). We find that for the beta-anomer of AP, the complex between (AP)6T6and the target site G6A6*T6C6is stable, generating a clear DNase I footprint at oligonucleotide concentrations as low as 0.25 microM at pH 5.0, in contrast to 50 microM C6T6which has no effect on the cleavage pattern. This complex is still stable at pH 6.5 producing a footprint with 1 microM oligonucleotide. Oligonucleotides containing the alpha-anomer of AP are much less effective than the beta-anomer, though in some instances they are more stable than the unmodified oligonucleotides. The results of molecular dynamics studies on a range of AP-containing triplexes has rationalized the observed stability behaviour in terms of hydrogen-bonding behaviour.

Efficient triple helix formation by oligodeoxyribonucleotides containing alpha- or beta-2-amino-5-(2-deoxy-D-ribofuranosyl) pyridine residues.

Triple helices containing C+xGxC triplets are destabilised at physiological pH due to the requirement for base protonation of 2'-deoxycytidine (dC), which has a pKa of 4.3. The C nucleoside 2-amino-5-(2'-deoxy-beta-D-ribofuranosyl)pyridine (beta-AP) is structurally analogous to dC but is considerably more basic, with a pKa of 5.93. We have synthesised 5'-psoralen linked oligodeoxyribonucleotides (ODNs) containing thymidine (dT) and either beta-AP or its alpha-anomer (alpha-AP) and have assessed their ability to form triplexes with a double-stranded target derived from standard deoxynucleotides (i.e. beta-anomers). Third strand ODNs derived from dT and beta-AP were found to have considerably higher binding affinities for the target than the corresponding ODNs derived from dT and either dC or 5-methyl-2'-deoxycytidine (5-Me-dC). ODNs containing dT and alpha-AP also showed enhanced triplex formation with the duplex target and, in addition are more stable in serum-containing medium than standard oligopyrimidine-derived ODNs or ODNs derived from dT and beta-AP. Molecular modelling studies showed that an alpha-anomeric AP nucleotide can be accommodated within an otherwise beta-anomeric triplex with only minor perturbation of the triplex structure. Molecular dynamics (MD) simulations on triplexes containing either the alpha- or beta-anomer of (N1-protonated) AP showed that in both cases the base retained two standard hydrogen bonds to its associated guanine when the 'A-type' model of the triplex was used as the start-point for the simulation, but that bifurcated hydrogen bonds resulted when the alternative 'B-type' triplex model was used. The lack of a differential stability between alpha-AP- and beta-AP-containing triplexes at pH >7, predicted from the behaviour of the B-type models, suggests that the A-type models are more appropriate.

Predicting the timing of first sexual intercourse for at-risk adolescent males.

Event history analysis was used to test a developmental model of the timing of first sexual intercourse in the Oregon Youth Study sample of adolescent males at risk for delinquency. The event history models spanned grades 7-12 with yearly multimethod, multiagent measures. A 3-step mediational model of predictors was tested, including contextual and process factors and boys' characteristics. Predictors included one-time measures of socioeconomic status, parental antisocial behavior, and time-varying measures of parental transitions, parental monitoring, deviant peer association, and the boys' antisocial/delinquent behavior, substance use, physical maturation, academic achievement, and anxiety. As predicted, antisocial/delinquent behavior and substance use along with early physical maturity and parental transitions predicted early onset of sexual intercourse. Anxiety was related to delay of first intercourse. Results and intervention implications are discussed in terms of the developmental findings.

Use of the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) and related protecting groups in oligoribonucleotide synthesis: stability of internucleotide linkages to aqueous acid.

The internucleotide linkage of uridylyl-(3'-->5')-uridine (r[UpU]) does not undergo detectable hydrolytic cleavage or migration in ca. 24 hr in 0.01 mol dm-3 hydrochloric acid (pH 2.0) at 25 degrees C. However, unlike r[UpU] and previously examined relatively high molecular weight oligoribonucleotides, oligouridylic acids are very sensitive to aqueous acid under the latter conditions (pH 2.0, 25 degrees C). Thus when the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp) group is used to protect the 2'-hydroxy functions in the synthesis of r[(Up)9U] and r[(Up)19U], the final unblocking process must be carried out above pH 3 if hydrolytic cleavage and migration are to be avoided. It is demonstrated that the rate of acid-catalyzed hydrolysis of the internucleotide linkages of oligoribonucleotides is sequence dependent. As Fpmp groups may be virtually completely removed from average partially-protected oligoribonucleotides within ca. 24 hr at pH 3 and 25 degrees C, it is concluded that Fpmp is a suitable 2'-protecting group even in the synthesis of particularly acid-sensitive sequences.

Aging, exercise, and attention.

The authors investigated the relationship among aging, attentional processes, and exercise in 2 experiments. First they examined age differences on 2 attentional tasks, a time-sharing task and an attentional flexibility task. Young adults alternated attention between 2 sequenced tasks more rapidly and time-shared the processing of 2 tasks more efficiently than older adults. They then investigated the effects of aerobic exercise on the same 2 attentional tasks in older adults. Following the 10-week exercise program, older exercisers showed substantially more improvement in alternation speed and time-sharing efficiency than older controls. Interestingly, this exercise effect was specific to dual-task processing. Both groups of subjects showed equivalent effects on single-task performance. These results indicate that aerobic exercise can exert a beneficial influence on the efficiency of at least 2 different attentional processes in older adults.