bluuebunny/crossref_metadata_2025 huggingface dataset:
Local Shear Stress and Brachial Artery Flow-Mediated Dilation
Authors: Mitchell Gary F. , Parise Helen , Vita Joseph A. , Larson Martin G. , Warner Elaine , Keaney John F. , Keyes Michelle J. , Levy Daniel , Vasan Ramachandran S. , Benjamin Emelia J.
Published: July 2004

Endothelium-dependent flow-mediated dilation is a homeostatic response to short-term increases in local shear stress. Flow-mediated dilation of the brachial artery in response to postischemic reactive hyperemia is impaired in patients with cardiovascular disease risk factors and may reflect local endothelial dysfunction in the brachial artery. However, previous studies have largely neglected the effect of risk factors on evoked shear stress, which is the stimulus for dilation. We evaluated brachial artery percent dilation and evoked diastolic shear stress during reactive hyperemia using high-resolution ultrasound and Doppler in 2045 participants (1107 women, mean age 61 years) in the Framingham Offspring Study. In age- and sex-adjusted models, baseline and hyperemic shear stress were related to brachial artery percent dilation. In stepwise multivariable analyses examining clinical correlates of percent dilation (without shear stress in the model), age, sex, mean arterial pressure, pulse pressure, heart rate, body mass index, lipid medication use, and hormone replacement therapy were related to percent dilation (
R

2

=0.189;
P
<0.001). When hyperemic shear stress was incorporated, the overall
R

2

improved (
R

2

=0.335;
P
<0.001), but relationships between risk factors and percent dilation were attenuated (age and mean arterial pressure) or no longer significant (all others). In contrast, risk factors were related to baseline and hyperemic shear stress in multivariable analyses. Evoked hyperemic shear stress is a major correlate of brachial artery flow-mediated dilation. The associations between many risk factors and brachial artery flow-mediated dilation may be attributable to reduced stimulus for dilation rather than impaired local conduit artery response during hyperemia.
Moderate Hyperhomocysteinemia Decreases Endothelial-Dependent Vasorelaxation in Pregnant But Not Nonpregnant Mice
Authors: Powers Robert W. , Gandley Robin E. , Lykins David L. , Roberts James M.
Published: July 2004

Increased homocysteine is associated with the pregnancy complication preeclampsia and with later-life cardiovascular disease. Although elevated homocysteine persists after pregnancy, the vascular changes of preeclampsia abate with delivery, and cardiovascular disease occurs decades later. This suggests the vasculature during pregnancy may manifest increased sensitivity to homocysteine. We used the cystathionine-β synthase (CBS)–deficient transgenic mouse to investigate whether hyperhomocysteinemia would differentially affect vascular function in nonpregnant and pregnant animals. Mesenteric arteries from nonpregnant and midpregnant (14 to 16 days) wild-type, heterozygous, and homozygous CBS-deficient transgenic mice were investigated for their response to vasoconstriction, endothelial-dependent, and endothelial-independent relaxation using an isometric wire myograph system. Endothelial-dependent vasodilation was similar in arteries from nonpregnant heterozygous and wild-type mice. In contrast, endothelial-dependent relaxation was reduced significantly in arteries from pregnant heterozygous animals compared with wild-type mice. Inhibition of NO synthesis blunted relaxation in arteries from pregnant wild-type but not pregnant heterozygous mice. Endothelial-dependent relaxation was restored by in vitro pretreatment with the tetrahydrobiopterin precursor sepiapterin. These data indicate that in pregnant mice, endothelial-dependent vasodilation is more sensitive to the effect of increased homocysteine than arteries from nonpregnant mice. This effect appears to result from a loss in NO-mediated relaxation that may be mediated by the oxidative inactivation of the NO synthase cofactor tetrahydrobiopterin.
Risk Taking and Novelty Seeking in Adolescence: Introduction to Part I
Authors: KELLEY ANN E. , SCHOCHET TERRI , LANDRY CHARLES F.
Published: July 2004

Abstract: Risk taking and novelty seeking are hallmarks of typical adolescent behavior. Adolescents seek new experiences and higher levels of rewarding stimulation, and often engage in risky behaviors, without considering future outcomes or consequences. These behaviors can have adaptive benefits with regard to the development of independence and survival without parental protection, but also render the adolescent more vulnerable to harm. Indeed, the risk of injury or death is higher during the adolescent period than in childhood or adulthood, and the incidence of depression, anxiety, drug use and addiction, and eating disorders increases. Brain pathways that play a key role in emotional regulation and cognitive function undergo distinct maturational changes during this transition period. It is clear that adolescents think and act differently from adults, yet relatively little is known about the precise mechanisms underlying neural, behavioral, and cognitive events during this period. Increased investigation of these dynamic alterations, particularly in prefrontal and related corticolimbic circuitry, may aid this understanding. Moreover, the investigation of mammalian animal models of adolescence—such as those examining impulsivity, reward sensitivity, and decision making—may also provide new opportunities for addressing the problem of adolescent vulnerability.
Risk Taking in Adolescence: What Changes, and Why?
Authors: STEINBERG LAURENCE
Published: July 2004

Abstract:Extant studies of age differences in cognitive processes relevant to risk taking and decision making, such as risk perception and risk appraisal, indicate few significant age differences in factors that might explain why adolescents engage in more risk taking than adults. The present analysis suggests that the greater propensity of adolescents to take risks is not due to age differences in risk perception or appraisal, but to age differences in psychosocial factors that influence self‐regulation. It is argued that adolescence is a period of heightened vulnerability to risk taking because of a disjunction between novelty and sensation seeking (both of which increase dramatically at puberty) and the development of self‐regulatory competence (which does not fully mature until early adulthood). This disjunction is biologically driven, normative, and unlikely to be remedied through educational interventions designed to change adolescents' perception, appraisal, or understanding of risk. Interventions should begin from the premise that adolescents are inherently more likely than adults to take risks, and should focus on reducing the harm associated with risk‐taking behavior.
Integrating Research on Developmental Psychopathology and Neuroscience in the Study of Adolescence: Introduction to Part II
Authors: PINE DANIEL S.
Published: July 2004

Abstract: This chapter introduces three papers that summarize research findings in clinical and basic neuroscience. They integrate prior research on clinical aspects of developmental psychopathology, basic research on brain development in nonhuman primates, and neuroimaging research on both normal and abnormal human development. From the clinical perspective these papers call attention to the unique relationship between adolescence and psychopathology. From the basic science perspective they call attention to the sequence of events that culminates in a fully mature central nervous system.
Structural Magnetic Resonance Imaging of the Adolescent Brain
Authors: GIEDD JAY N.
Published: July 2004

Abstract: Magnetic resonance imaging (MRI) provides accurate anatomical brain images without the use of ionizing radiation, allowing longitudinal studies of brain morphometry during adolescent development. Results from an ongoing brain imaging project being conducted at the Child Psychiatry Branch of the National Institute of Mental Health indicate dynamic changes in brain anatomy throughout adolescence. White matter increases in a roughly linear pattern, with minor differences in slope in the four major lobes (frontal, parietal, temporal, occipital). Cortical gray matter follows an inverted U‐shape developmental course with greater regional variation than white matter. For instance, frontal gray matter volume peaks at about age 11.0 years in girls and 12.1 years in boys, whereas temporal gray matter volume peaks at about age at 16.7 years in girls and 16.2 years in boys. The dorsal lateral prefrontal cortex, important for controlling impulses, is among the latest brain regions to mature without reaching adult dimensions until the early 20s. The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.
Neuroimaging of Developmental Psychopathologies: The Importance of Self‐Regulatory and Neuroplastic Processes in Adolescence
Authors: SPESSOT ALEXANDRA L. , PLESSEN KERSTIN J. , PETERSON BRADLEY S.
Published: July 2004

Abstract: Normal brain maturational and developmental processes, together with plastic reorganization of the brain in response to experiential demands, contribute to the acquisition of improved capacities for self‐regulation and impulse control during adolescence. The frontal lobe is a main focus for these developmental and plastic processes during the transition from adolescence into adulthood. Tourette syndrome (TS), defined as the chronic presence of motor and vocal tics, has been increasingly conceptualized as a disorder of impaired self‐regulatory control. This disordered control is thought to give rise to semicompulsory urges to perform the movements that constitute simple tics, complex tics, or compulsions. Neuroimaging studies suggest that the expression of the genetic diathesis to TS is influenced by genetic and nongenetic factors affecting activity‐dependent reorganization of neuroregulatory systems, thereby influencing the phenotype, illness severity, and adult outcome of tic disorders. Similar developmental processes during adolescence likely determine the phenotype and natural history of a broad range of other complex neuropsychiatric disorders of childhood onset, and they likely contribute to the acquisition of improved self‐regulatory capacities that characterize normal adolescent development.
Interrelationships between Hormones, Behavior, and Affect during Adolescence: Understanding Hormonal, Physical, and Brain Changes Occurring in Association with Pubertal Activation of the Reproductive Axis. Introduction to Part III
Authors: CAMERON JUDY L.
Published: July 2004

Abstract: This paper summarizes the goals of this section and considers current knowledge about the association between hormonal changes that occur over pubertal development and the changes in behavior and brain function over the adolescent period. It reviews the cascade of neural and hormonal changes that occur with puberty; discusses mechanisms by which these changes can affect higher‐order brain processes; reviews the current limited state of knowledge about links between puberty and changes in affect regulation in the adolescent period; identifies hurdles that have made progress in our understanding of these relationships difficult; and suggests areas for future investigation that will allow us to obtain a much more comprehensive understanding of these interrelationships. This overview of the physiological processes occurring at puberty indicates that puberty (1) encompasses changes in a number of neural systems; (2) results in altered secretion of a number of hormones; (3) involves hormones that are secreted in a pulsatile manner so that collection of a single blood sample does not clearly delineate hormone profiles; and (4) shows considerable individual variation in the rate of progression and in hormone secretion during progression. The important role that gonadal steroid hormones play throughout development and adulthood in regulating plastic changes in neuronal structure and function is noted, highlighting the need for further studies to determine the extent to which the dramatic increases in circulating steroid hormones at puberty modulate brain circuits that underlie changes in social behaviors, risk‐taking behaviors, and cognitive function at adolescence.
Adolescence: Vulnerable Period for Stress‐Induced Prefrontal Cortical Function? Introduction to Part IV
Authors: ARNSTEN AMY F. T. , SHANSKY REBECCA M.
Published: July 2004

Abstract: Exposure to even mild uncontrollable stress impairs the cognitive functioning of the prefrontal cortex, a brain region critical for insight, judgment, and the inhibition of inappropriate behaviors. Several neurobiological factors may contribute to an exaggeration of the stress response in adolescence, for example, an increased dopaminergic projection to prefrontal cortex, and in females, increased circulating estrogen, as estrogen amplifies many aspects of the stress response and lowers the threshold for stress‐induced prefrontal cortical dysfunction. These neurobiological factors may increase susceptibility to impaired judgment, drug addiction, and neuropsychiatric disorders during adolescence.
The Importance of Adolescence in the Development of Nicotine Dependence: Introduction to Part V
Authors: CLAYTON RICHARD R.
Published: July 2004

Abstract: This article sets the stage for the papers in Part V by describing the research work of the Tobacco Etiology Research Network (TERN), an ititiative of the Robert Wood Johnson Foundation. Two studies coming from this matrix include one on the acquisition of tobacco use and another on the trajectories of tobacco use among college freshman.
Individual and Contextual Influences on Adolescent Smoking
Authors: TURNER LINDSEY , MERMELSTEIN ROBIN , FLAY BRIAN
Published: July 2004

Abstract:Cigarette smoking among adolescents remains one of the most important public health challenges. Despite much attention to research on the etiology of smoking, notably the examination of factors that differentiate adolescent smokers from never smokers, much less is known about factors that predict the development of dependence once an adolescent tries smoking. This paper reviews individual and contextual influences on the progression of smoking among adolescents. Highlights include a consideration of multiple levels of influence, from intra‐individual factors, such as genetics, demographics, temperament and comorbidities, to social influences, such as families and peers, to the more macro, societal/cultural levels of influence, including advertising and tobacco‐related policies. More recent work examining microcontextual influences through the use of Ecological Momentary Assessments is also discussed. Finally, the need to consider both developmental and transdisciplinary approaches to understanding the development of nicotine dependence in adolescents is emphasized.
Hippocampal Function during Adolescence: A Unique Target of Ethanol Effects
Authors: WHITE AARON M. , SWARTZWELDER H SCOTT
Published: July 2004

Abstract: Behaviors mediated by the hippocampus have long been known to be sensitive to the acute, chronic, and prenatal effects of ethanol. It has recently become clear that hippocampal function is uniquely responsive to ethanol during periadolescent development, and that alcohol affects behavior and brain function differently in adolescents and adults. We have used behavioral techniques, as well as extracellular and whole‐cell electrophysiological techniques, to assess the effects of acute and chronic ethanol exposure on hippocampal function during adolescence and adulthood. Our results are consistent with the view that the hippocampus is more sensitive to the acute effects of ethanol during adolescence and may be more susceptible to the neurotoxic effects of ethanol during this developmental period. Studies of this type have yielded valuable information for prevention, education, and public policy efforts related to underage drinking.
Adolescent Development and the Regulation of Behavior and Emotion: Introduction to Part VIII
Authors: DAHL RONALD E.
Published: July 2004

Abstract: This article introduces and identifies key issues in the articles in this section.
Regulatory Processes, Risk, and Resilience in Adolescent Development
Authors: MASTEN ANN S.
Published: July 2004

Abstract: This article highlights the potential of developmental psychopathology as a useful integrative perspective for the challenging task of linking the study of brain development and adolescent behavior in context; it considers clues from behavioral research on resilience on the nature of regulatory processes as risks and assets, or vulnerabilities and protective factors for the development of competence and psychopathology in adolescence; and it advocates more integrative neurobehavioral research on risk and resilience in adolescent development.
Development of Error‐Monitoring Event‐Related Potentials in Adolescents
Authors: DAVIES PATRICIA L. , SEGALOWITZ SIDNEY J. , GAVIN WILLIAM J.
Published: July 2004

Abstract: In order to study the maturation of neurobehavioral systems involved in affect regulation and behavioral choices during adolescence, we examined brain activity associated with response monitoring and error detection using event‐related potentials (ERPs). In a visual flanker test, trials with incorrect responses elicit ERP components including an error‐related negativity (ERN) and a later error‐positivity (Pe). We examined the amplitude and latency of the ERN and Pe of incorrect responses in 124 children from 7 to 18 years of age. The ERN amplitude in error trials increased with age although this was qualified by a nonlinear change. The quadratic distribution of the ERN indicated an initial drop in amplitude (lowest at age 10 for girls; age 13 for boys) with a subsequent rise through adolescence. The Pe amplitude did not change with age. Results are discussed with respect to continued maturation of the anterior cingulate cortex and possible influences on adolescent behaviors.
Positive and Negative Affect in Depression: Influence of Sex and Puberty
Authors: FORBES ERIKA E. , WILLIAMSON DOUGLAS E. , RYAN NEAL D. , DAHL RONALD E.
Published: July 2004

Abstract: To examine adolescent depression as a model for unusual emotion regulation, the current study considered the influence of gender, pubertal development, and cortisol on self‐reported mood. Children and adolescents with major depressive disorder (n= 35, mean age 12.5 years) were compared with psychiatrically healthy children and adolescents (n= 36, mean age 10.5 years). During a three‐day assessment, participants rated their mood at three time points, pubertal development was determined through physical examination, and plasma cortisol was sampled during the second night. Depressed participants experienced less positive affect and more negative affect than did controls. Diagnostic group, gender, and pubertal status interacted to predict negative affect, with depressed adolescent girls experiencing especially high levels of negative affect. Cortisol was generally unrelated to depression and mood. Findings are consistent with emotion‐based models of depression and with the literature on depression and emotion regulation during adolescence.
Sleep Hygiene and Sleep Quality in Italian and American Adolescents
Authors: LEBOURGEOIS MONIQUE K. , GIANNOTTI FLAVIA , CORTESI FLAVIA , WOLFSON AMY , HARSH JOHN
Published: July 2004

Abstract: This study investigated cross‐cultural differences in adolescent sleep hygiene and sleep quality. Participants were 1348 students (655 males; 693 females) aged 12‐17 years from public school systems in Rome, Italy (n= 776) and Southern Mississippi (n= 572). Participants completed the Adolescent Sleep‐Wake Scale and the Adolescent Sleep Hygiene Scale. Reported sleep hygiene and sleep quality were significantly better for Italian than American adolescents. A moderate linear relationship was observed between sleep hygiene and sleep quality in both samples (Italians: R= .40; Americans: R= .46). Separate hierarchical multiple regression analyses showed that sleep hygiene accounted for significant variance in sleep quality, even after controlling for demographic and health variables (Italians: R2= .38; Americans: R2= .44). The results of this study suggest that there are cultural differences in sleep quality and sleep hygiene practices, and that sleep hygiene practices are importantly related to adolescent sleep quality.
Trajectories of Adolescent Emotional and Cognitive Development: Effects of Sex and Risk for Drug Use
Authors: SILVERI MARISA M. , TZILOS GOLFO K. , PIMENTEL PATRICIA J. , YURGELUN‐TODD DEBORAH A.
Published: July 2004

Abstract: Adolescence has been widely accepted as a time for notable alterations in brain functioning. The objective of this longitudinal study was to compare trajectories of emotional and cognitive development in adolescent girls and boys with low‐ versus high‐risk for future drug use. Nineteen healthy adolescents (aged 13.9 ± 2.0 years; 10 girls), stratified into low‐ and high‐risk groups based on family history of drug abuse, were examined at baseline and after one year. Emotional intelligence was assessed using the Bar‐On Emotional Quotient Inventory, the Multidimensional Anxiety Scale for Children, and the Perceived Stress Scale. The neurocognitive test battery was designed to evaluate academic achievement, executive function, verbal memory and learning, and included the Wide Range Achievement Test, Stroop Color‐Word Interference Test, Rey Auditory Verbal Learning Test, and Digit Span and Digit Symbol subtests of the Wechsler Adult Intelligence Scale‐Revised. Improvements in academic achievement, executive function, and working memory were observed at the one‐year follow‐up. Notable sex differences also were evident in emotional intelligence, academic achievement, and memory. Interestingly, these sex‐related differences interacted with risk status; improvement in cognitive performance in boys and low‐risk girls was generally superior to high‐risk girls, who tended to show modest, if any, improvement at the one‐year follow‐up. These preliminary findings provide evidence of sex differences in emotion intelligence and cognitive function. Furthermore, these data also suggest that history of familial drug abuse may have a more pronounced impact on emotional and cognitive development in adolescent girls than boys.
Impact of Cannabis Use on Brain Function in Adolescents
Authors: JACOBSEN LESLIE K. , MENCL W EINAR , WESTERVELD MICHAEL , PUGH KENNETH R.
Published: July 2004

Abstract: Cannabis is the most common illicit substance used by adolescents. This paper reports results of a pilot study using fMRI and a working memory task to compare brain function of adolescent cannabis users to that of two control groups, one matched for tobacco use and the other for nonsmokers.
Nicotine Administration Significantly Alters Accumbal Dopamine in the Adult but Not in the Adolescent Rat
Authors: BADANICH KIMBERLY A. , KIRSTEIN CHERYL L.
Published: July 2004

Abstract: Many drug‐dependent adults began using drugs during adolescence. In fact, adolescent drug users are more likely to become drug‐dependent adults than those abstaining from drug use until after the age of 18. Because of this, recent research has begun to investigate the consequences of adolescent drug use. Specifically, research has begun to focus on the behavioral effects of drugs on the developing brain and the development of drug addiction. The present study examined the responsiveness of the mesolimbic dopamine (DA) pathway during development through the use of in vivo microdialysis. Specificall, it was determined whether nicotine‐induced accumbal DA release differs between adolescent and adult rats. To assess nicotine's effects across age, animals received acute or repeated nicotine at early adolescence (postnatal day (PND) 35), late adolescence (PND 45), or young adulthood (PND 60). Findings suggest that there are significant differences between adolescent and adult animals in their dopaminergic response to nicotine. Adult animals had an enhanced DA response to acute nicotine challenge, an effect absent in adolescence. Additionally, this nicotine‐induced increase in adults was not apparent after repeated nicotine treatment. These results provide insight into how the adolescent brain responds to nicotine and may also provide evidence as to how prolonged nicotine use affects normal brain development and responsiveness.
Grid Crossing: Inability to Compare Activity Levels between Adolescent and Adult Rats
Authors: VILA J L , PHILPOT R M , KIRSTEIN C L
Published: July 2004

Abstract: Traditionally, studies measuring behavioral activity have used male adult animals and grid crossings (GCs) as a representative measure of activity in lieu of total distance moved (TDM). However, using GCs as the dependent measure may not be effective for comparing the activity of animals during development, as they vary significantly in size. The present study examines the reliability of GCs as opposed to TDM as an indicator of locomotor activity for comparisons during ontogeny using a computerized behavioral tracking system (Noldus). Rats (postnatal day[PND] 35, PND 60) were tracked for a period of 3 minutes inside a closed runway. GCs and TDM were measured for the recorded tracks. It was determined that GCs were positively correlated with TDM in the behavioral apparatus, suggesting that GCs is a reliable measure of an individual animal's activity. Using GCs as the dependent measure, no significant differences in activity were observed across age or sex. However, using TDM indicates adolescent rats are significantly more active than their adult counterparts. These data indicate that although the number of GCs is predictive of total activity, the slope of the relationship varies significantly with age, therefore making it inappropriate to use GCs when comparing across ages. Studies that use animals of differing age must be sensitive to baseline differences in locomotor activity.
Developmental Differences in the Accumbal Dopaminergic Response to Repeated Ethanol Exposure
Authors: PHILPOT REX , KIRSTEIN CHERYL
Published: July 2004

Abstract: Recent research indicates that alcohol use/abuse is often initiated during the adolescent period and that brain reinforcement pathways (e.g., the mesolimbic dopamine [DA] pathway) are undergoing developmental transition. Our research focuses on the effects of ethanol administration on neural mechanisms associated with addiction in preadolescent (postnatal day [PND] 25), adolescent (PND 35, PND 45), and young adult (PND 60) animals. Using conditioned place preference (CPP) testing, we have shown that adolescent animals are unique in their responses to ethanol. Since CPP has been associated with contextually conditioned incentive motivation, our results suggest that younger animals may be more vulnerable to addiction. The present data reveal that adolescent animals are neurochemically distinct in response to ethanol's effects. Using in vivo microdialysis within the nucleus accumbens septi (NAcc), we have determined the DAergic response across development. Results reveal that basal levels of DA transition during the adolescent period and differ from preadolescent or adult animals. Specifically, PND 45 animals exhibited significantly higher, and PND 25 significantly lower, basal DA levels than all other ages examined. Further, repeated exposure to ethanol elevated basal DA levels significantly regardless of age or dose. Basal 3,4‐dihydroxyphenylacetic acid (DOPAC)/DA ratio also differed as a function of age, with PND 35 and PND 60 animals demonstrating the highest ratios, and PND 45 animals producing the lowest baseline levels. Repeated ethanol exposure produced significant changes in basal ratios as a function of age. Interestingly, PND 45 animals exhibited no change in ratios with repeated exposure, while all other ages demonstrated a dose‐dependent rise in DOPAC/DA ratios. These data indicate an age‐dependent difference in the homeostatic alterations of mesolimbic systems in response to repeated ethanol treatment, an effect that may manifest itself as differences in behavioral responsivity and conditionability to the drug and the drug's effects.
13‐cis Retinoic Acid (Accutane) Suppresses Hippocampal Cell Survival in Mice
Authors: SAKAI YASUO , CRANDALL JAMES E. , BRODSKY JACOB , MCCAFFERY PETER
Published: July 2004

Abstract: Use of the acne drug Accutane (13‐cis retinoic acid, [13‐cis RA]) has been associated with severe depression. This association has been considered controversial because no causative link has been found between 13‐cis RA and this disorder. A recent hypothesis has suggested that atrophy of the hippocampus can result in depression. We now show, in a mouse model, that endogenous RA generated by synthetic enzymes in the meninges acts on hippocampal granule neurons, and chronic (3‐week) exposure to a clinical dose of 13‐cis RA may result in hippocampal cell loss. In humans this may be conjectured to be the mechanism by which Accutane contributes to depression.
The Effects of Ethanol on Spatial and Nonspatial Memory in Adolescent and Adult Rats Studied Using an Appetitive Paradigm
Authors: RAJENDRAN P , SPEAR L P
Published: July 2004

Abstract: Adolescent rats have been reported to be less sensitive than adults to many acute ethanol effects, including ethanol‐induced sedation and motor impairment, but conversely more sensitive to ethanol‐induced disruptions in spatial memory in a Morris water maze (Markwiese et al., 1998). The present study examined adolescent and adult rats trained for 6 days under spatial or nonspatial versions of a presumably less stressful sand box maze. Moderately food‐deprived animals were given 0, 0.5, or 1.5 g/kg ethanol intraperitoneally 30 min before training each day, but were tested without ethanol or reinforcer on test day. Spatial acquisition was impaired by 1.5 g/kg in adults but not adolescents, with no ethanol impairment on the nonspatial task at either age. These results are opposite the ontogenetic profile reported by Markwiese et al., (1998) and may reflect differential activation of prefrontal cortex or other stress‐sensitive forebrain regions by the two tasks across age.
Adolescent Ethanol Sensitivity: Hypothermia and Acute Tolerance
Authors: RISTUCCIA R C , SPEAR L P
Published: July 2004

Abstract: A two‐injection paradigm was used to assess acute (within‐session) tolerance to ethanol in telemetry‐implanted adolescent and adult rats. Male rats were intragastrically pretreated with either 1.0 g/kg of ethanol or water and then challenged with 2.0 g/kg of ethanol or water when blood alcohol levels (BALs) of ethanol‐pretreated animals were anticipated to approach zero. Adults showed more rapid and sustained ethanol‐induced hypothermia than adolescents. Acute tolerance to ethanol‐induced hypothermia did not emerge clearly with the two‐injection paradigm; ethanol‐pretreated animals of both ages generally did not differ from those pretreated with water in their hypothermic response to ethanol despite higher BALs after the second intubation. Housing condition (paired or isolated) had little influence on ethanol‐induced hypothermia. The adolescent attenuation of ethanol‐induced hypothermia in this experiment was not associated with greater expression of within‐session (acute) tolerance.
An Animal Model of Sensation Seeking: The Adolescent Rat
Authors: STANSFIELD KIRSTIE H. , PHILPOT REX M. , KIRSTEIN CHERYL L.
Published: July 2004

Abstract: Previous research has established a strong relationship between a rodent's preference for novelty and sensitivity to psychomotor stimulants. Rats with greater sensitivity to the motoric effects of amphetamine exhibit higher preferences for novelty. Additionally, animals with high novelty preference scores are more easily drug conditioned and are more sensitive to, and can more accurately discriminate, amphetamine doses. Novelty preference in animals has been compared to sensation seeking in humans and is strongly correlated with drug use and addiction vulnerability. Thus, the present studies employed a playground maze procedure to measure changes in novelty preference across age following either four or eight habituation trials using eight distinct objects. Early‐adult (postnatal day [PND] 59) animals did not exhibit a significant preference for a novel object regardless of total number of habituation trials. Early‐adolescent animals (PND 34) exhibited a preference for the novel object in fewer than four habituation trials, but exhibited no preference with increased habituation trials. These results are counterintuitive and may demonstrate an overgeneralization of the habituation trials specific to adolescent animals. Given that adolescence is a period of heightened exploration, one would expect adolescent animals to demonstrate an enhanced preference for novel stimuli using this paradigm. However, it is possible that the complexity of the task, as presented, reveals differences in the establishment and behavioral manifestation of associations during adolescence. To address this issue, a separate novelty paradigm was implemented using an open‐field habituation procedure followed by the introduction of a single novel object during the testing period. This revised design provides the foundation needed to better assess novelty‐induced locomotor activity and novelty preference in adolescent rats.
Adolescent and Adult Rats' Aversion to Flavors Previously Paired with Nicotine
Authors: WILMOUTH CARRIE E. , SPEAR LINDA P.
Published: July 2004

Abstract: Despite the high prevalence of adolescent smoking, few studies have examined nicotine sensitivity during this developmental period. In the present study we examined adolescent and adult rats' preference/aversion for a flavor previously paired with nicotine. Paired (nicotine + Kool‐Aid) and unpaired (Kool‐Aid) solutions were presented in the home cage on alternating nights, with water given during the light phase for six days. A choice test was conducted 24 hr after the last night of conditioning, with both flavors presented simultaneously during the dark cycle. On test day, although the flavor previously paired with nicotine was not preferred at either age, adolescent rats consumed significantly more of the paired flavor than adults. These results suggest that adolescent rats are less sensitive to the aversive properties of nicotine. This finding taken together with adolescents' increased sensitivity to the rewarding properties of nicotine, may result in an increased vulnerability to nicotine dependence.
Challenges for Biomarkers in Cancer Detection
Authors: WAGNER PAUL D. , VERMA MUKESH , SRIVASTAVA SUDHIR
Published: July 2004

Abstract: Cancer remains the leading cause of death in the United States. Biomarkers can be used to detect cancer in different stages, initiation, development, and progression. The desirable property and utility of a biomarker lie in its ability to provide an early indication of disease progression. Biomarkers should be easy to detect, measurable across populations, and useful for detection of cancer at an early stage, identification of high‐risk individuals, detection of recurrence, or monitoring endpoints in intervention studies. Recent technological advances have helped develop noninvasive, sensitive, and specific biomarkers to detect cancer at early stages of the disease.
Detection and Characterization of Circulating Microsatellite‐DNA in Blood of Patients with Breast Cancer
Authors: SCHWARZENBACH HEIDI , MÜLLER VOLKMAR , STAHMANN NICOLE , PANTEL KLAUS
Published: July 2004

Abstract:Increased levels of circulating DNA have been reported in the blood of cancer patients but not healthy individuals. Tumor‐specific genomic aberrations, such as loss of heterozygosity (LOH) and microsatellite instability (MSI), can be detected in this free extracellular DNA. Identification of these genetic aberrations may play an important role in cancer diagnosis and prediction of disease progression. Moreover, the genomic regions involved might harbor potential targets for therapies. To evaluate the incidence of microsatellite alterations in circulating DNA, we assessed the blood serum of 34 patients with primary (n= 8) and metastatic (n= 24) breast cancer. Samples were also analyzed for the presence of circulating tumor cells using an immunocytological cytokeratin assay, and the concentration of the tumor marker CA 15‐3 was determined. Genomic DNA extracted from serum and normal blood leukocytes, as a control, was amplified by the polymerase chain reaction using markers at 4 microsatellite loci of chromosomes 10q22‐23, 16q22‐23, 17q11‐12, and 17q21. In 17 of 34 cancer patients, tumor‐specific alterations were detected in serum samples. In 16 patients, LOH at various loci was observed, whereas MSI was only detected in the serum of one patient. The pattern of LOH was very heterogeneous, and LOH was detected at chromosomal loci 10q22‐23, 16q22‐23, and 17q11‐12 but not 17q21. No correlation was found between the detection of circulating tumor DNA and the presence of circulating tumor cells in the blood or serum concentration of CA 15–3. In conclusion, genomic aberrations on chromosomes 10, 16, and 17 are frequent in the circulating DNA of breast cancer patients. However, circulating tumor DNA does not reflect the presence of tumor cells in blood or the level of tumor‐associated protein markers such as CA 15–3. Thus, screening for circulating tumor DNA may provide additional diagnostic information.
Role of Cell‐Free Plasma DNA as a Diagnostic Marker for Prostate Cancer
Authors: ALLEN DARRELL , BUTT ASIF , CAHILL DECLAN , WHEELER MIKE , POPERT RICK , SWAMINATHAN R
Published: July 2004

Abstract: Recent evidence has shown elevated levels of cell‐free plasma DNA in cancer patients. The aim of the present study was to quantify and compare the levels of cell‐free plasma DNA in patients with prostate cancer, prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) to examine if it offered a useful diagnostic test. Blood samples were obtained from 37 patients attending a clinic for prostate biopsies. Samples were taken prior to biopsy, within 1 hour of the biopsy, and then 2 weeks later. DNA was extracted using a QIAamp blood kit (Qiagen) and plasma DNA measured, in genome equivalents/milliliter plasma (GE/mL), using real‐time quantitative PCR for the β‐globin gene. Prior to biopsy, plasma DNA concentration in BPH patients was 936 GE/mL (median; range: 633–2074 GE/mL), while cancer and PIN patients had significantly higher levels of DNA at 1734 GE/mL (median; range: 351–3131 GE/mL; P= 0.01) and 1780 GE/mL (median; range: 1514‐2732 GE/mL; P= 0.04), respectively. Comparison of plasma DNA concentration before and after biopsy showed that 60 minutes after biopsy values were significantly higher in both BPH (1494 GE/mL; range: 613‐2522 GE/mL; P= 0.029) and cancer (2758; range: 1498‐5226 GE/mL; P= 0.007) patients. ROC analysis of the data indicated a sensitivity of 85% and a specificity of 73% when DNA concentration of 1000 GE/mL was taken as an indicator of malignancy or PIN. The data suggest that quantification of cell‐free plasma DNA may have an important diagnostic role in distinguishing benign and malignant prostate disease.
Fetal Cell‐Free Nucleic Acids in the Maternal Circulation: New Clinical Applications
Authors: WATAGANARA TUANGSIT , BIANCHI DIANA W.
Published: July 2004

Abstract: Six years after the demonstration of the presence of cell‐free fetal nucleic acids in maternal plasma, perinatal clinical applications continue to expand. The focus of this article is on advances that have occurred since the CNAPS II conference held in Hong Kong in 2001. Circulating fetal DNA levels (fDNA) are elevated in pregnancies complicated by fetal trisomies 13 and 21 but not 18. Measurement of fDNA levels improves the performance of the current standard maternal serum screen, by increasing the detection of Down syndrome cases by 5% with no increase in the false‐positive rate. fDNA levels are elevated in women who have developed clinical symptoms of preeclampsia, but they are also elevated by the early second trimester in women who will eventually develop preeclampsia. fDNA and mRNA gamma globin measurement may have clinical utility as markers for fetomaternal hemorrhage in the late first trimester. Cell‐free fetal DNA levels are quite high in the amniotic fluid, permitting fetal genomic isolation and analysis using comparative genomic hybridization techniques. Fetal DNA crosses the blood‐brain barrier and is detectable in maternal cerebrospinal fluid in a subset of pregnant women. The biological implications of this are currently unknown. Review of the literature suggests that the placenta is the predominant source of the circulating fetal nucleic acids. However, detection of gamma globin mRNA sequences in the plasma of pregnant women suggests that fetal blood cells also contribute to the pool of nucleic acids. Widespread incorporation of fetal nucleic acid measurement into routine prenatal care depends on the identification of a readily accessible gender‐independent fetal marker.
Circulating Nucleic Acids in Plasma/Serum III and Serum Proteomics Recent Developments in Fetal DNA in Maternal Plasma
Authors: CHIU ROSSA W.K. , LO Y M DENNIS
Published: July 2004

Abstract: It has been several years since the presence of fetal DNA in maternal plasma was first discovered. Numerous potential applications have been reported to date. However, the study of maternal plasma for the prenatal diagnosis of fetal genetic traits has largely centered on paternally inherited autosomal dominant traits. Recently, a number of approaches have been developed that allow the prenatal assessment of autosomal recessive conditions through fetal DNA analysis in maternal plasma. On the other hand, aberrations in fetal DNA concentrations in maternal plasma have been reported in a number of pregnancy‐associated conditions. Recent studies have begun to address the possible underlying mechanisms causing such quantitative aberrations. Current studies on circulating fetal DNA have focused on the detection of the paternally inherited fetal‐specific alleles in maternal plasma. However, it has been demonstrated that the development of fetal epigenetic markers has great potential to expand the field.
Feasibility Study for a Microchip‐Based Approach for Noninvasive Prenatal Diagnosis of Genetic Diseases
Authors: CREMONESI L , GALBIATI S , FOGLIENI B , SMID M , GAMBINI D , FERRARI A , VIORA E , CAMPOGRANDE M , PAGLIANO M , TRAVI M , PIGA A , RESTAGNO G , FERRARI M
Published: July 2004

Abstract: Fetal DNA in maternal plasma may represent a source of genetic material for prenatal noninvasive diagnosis of genetic diseases. We evaluated a cohort of physiological pregnancies to determine if fetal DNA can be retrieved at any gestational week in sufficient quantity to be analyzed with advanced mutation detection technologies. We performed fetal DNA quantification by real‐time polymerase chain reaction (PCR) on the SRY gene in 356 women sampled from 6 to 40 gestational weeks. Fetal DNA was retrieved at any week. All female fetuses were correctly identified. In 5 of 188 (2.6%) male‐bearing pregnancies, no amplification was obtained. For noninvasive testing, complete clearance of fetal DNA after delivery is mandatory. Long‐term persistence was not detected in women with previous sons or abortions. These findings confirm that maternal plasma may represent the optimal source of fetal genetic material. For noninvasive diagnosis of genetic diseases, we evaluated microchip technology. The detection limit for a minority allele determined by diluting a mutated DNA into a wild‐type plasma sample was 5 genome equivalents, indicating that the test might be applied to the identification of paternally inherited fetal alleles in maternal plasma. The addition of peptide nucleic acids (PNAs) to either the PCR reaction or the chip hybridization mixture allowed approximately 50% inhibition of wild‐type allele signals.
Rapid Clearance of Fetal Cells from Maternal Circulation after Delivery
Authors: KOLIALEXI AGGELIKI , TSANGARIS GEORGE TH. , ANTSAKLIS ARISTIDES , MAVROUA ARIADNI
Published: July 2004

Abstract: We previously reported increased apoptosis in the maternal circulation during pregnancy, partly accounting for the presence of cell‐free fetal DNA in maternal plasma. In the current study, apoptosis was quantitated in 60 peripheral blood samples obtained from 15 women sequentially tested postpartum using the binding of annexin V. FISH with X/Y probes was performed on annexin V‐positive cells isolated by MACS in patients with male fetuses to estimate the proportion of fetal cells among the apoptotic cell population. Twenty‐four women at the thirty‐seventh to thirth‐eighth week of gestation and 35 nonpregnant females were used as controls. Apoptosis rate in the thirty‐seventh to thirty‐eighth week was 12.5% (9.2‐14.7%). At 30 minutes, 12 hours, 24 hours, and 48 hours postpartum, it was 25.1% (16.8‐28.5%), 12.5% (10.9‐14.1%), 6.1% (4.8‐7.1%), and 2.3% (1.3‐3.0%), respectively. Male apoptotic cells were identified in all cases with male fetuses at 37 to 38 weeks of gestation, and the mean proportion was 9.9% (5.9‐13.2%). The proportion of fetal cells 30 minutes after delivery was 14.8% (12.5‐25.5%) and 12 hours postpartum 2.1% (0.8–4.1%). Male fetal apoptotic cells were detected in three of eight samples collected 24 hours after delivery from women who delivered males, at frequencies of 0.10%, 0.15%, and 0.25% (mean 0.16%). There were no fetal apoptotic cells 48 hours after delivery. Apoptosis partly accounts for the clearance of fetal cells from the maternal circulation. Because it is a rapid reaction, completed within 2–3 hours, persistence of fetal cells is possibly due to apoptosis‐resistant progenitors or to defective regulation of apoptosis, leading to fetal cell microchimerism associated with autoimmune diseases.
Can Circulatory Fetal DNA Be Used to Study Placentation at High Altitude?
Authors: ZHONG XIAO YAN , WANG YIMING , CHEN SUQIN , LABU  , PUBUZHUOMA  , GESANGZHUOGAB  , OUZHUWANGMU  , HAHN CORNELIA , HOLZGREVE WOLFGANG , HAHN SINUHE
Published: July 2004

Abstract: Pregnancy at high altitude (>2700 m) is associated with higher rates of fetal growth restriction and preeclampsia as well as alterations in placentation, including increased villous vascularization and reduced remodeling of maternal spiral arteries. Because circulatory fetal DNA concentrations were shown to be enhanced in pregnancies affected by preeclampsia, we investigated whether similar elevations are also apparent in pregnancies at high altitude by examining ethnic Tibetans and recent migrant Han Chinese residents in Lhasa (altitude 3650 m) as well as Han Chinese residents in Guangzhou (altitude 7 m). Our data from this preliminary study (n= 10/study group) indicate that circulatory fetal DNA levels were significantly higher in the unremarkable pregnancies of Han women who moved to Tibet when compared to Han women at sea level. No significant difference could be discerned between migrant Han Chinese and ethnic Tibetans living in Lhasa. Our data, therefore, suggest that pregnancy at high altitude is associated with an increased liberation of cell‐free fetal DNA and that no major ethnic differences are apparent.