bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11C‐doxepin in a placebo‐controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen
Authors: Tashiro Manabu , Mochizuki Hideki , Sakurada Yumiko , Ishii Kenji , Oda Keiichi , Kimura Yuichi , Sasaki Toru , Ishiwata Kiichi , Yanai Kazuhiko
Published: December 2005

Aims

The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second‐generation antihistamine and to compare it with that of ketotifen.

Methods

Eight healthy males (mean age 23.5 years‐old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C‐doxepin in a placebo‐controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined.

Results

H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001).

Conclusion

It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders.

Abbreviations

histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood–brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)
Effect of rifampicin on the pharmacokinetics of pioglitazone
Authors: Jaakkola Tiina , Backman Janne T. , Neuvonen Mikko , Laitila Jouko , Neuvonen Pertti J.
Published: December 2005

Aims

The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans.

Methods

In a randomized, two‐phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M‐IV and M‐III into urine were measured up to 48 h.

Results

Rifampicin decreased the mean total area under the plasma concentration‐time curve (AUC0−∞) of pioglitazone by 54% (range 20–66%; P = 0.0007; 95% confidence interval −78 to −30%) and shortened its dominant elimination half‐life (t1/2) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (Cmax) or time to peak (tmax) was observed. Rifampicin increased the apparent formation rate of M‐IV and shortened its tmax (P < 0.01). It also decreased the AUC0−∞ of M‐IV (by 34%; P = 0.0055) and M‐III (by 39%; P = 0.0026), shortened their t1/2 (M‐IV by 50%; P = 0.0008, and M‐III by 55%; P = 0.0016) and increased the AUC0−∞ ratios of M‐IV and M‐III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M‐IV/pioglitazone and M‐III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M‐XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M‐XI to pioglitazone by 240% (P = 0.0020).

Conclusions

Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.
The impact ofCYP2C8polymorphism and grapefruit juice on the pharmacokinetics of repaglinide
Authors: Bidstrup Tanja Busk , Damkier Per , Olsen Anette Kristensen , Ekblom Marianne , Karlsson Anders , Brøsen Kim
Published: December 2005

Aims

The primary aim of the study was to investigate the possible effect of theCYP2C8*3allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose.

Methods

Thirty‐six healthy male subjects, genotyped forCYP2C8*3(11 genotyped asCYP2C8*1/*3, one asCYP2C8*3/*3 and24 asCYP2C8*1/*1), participated in a randomized, cross‐over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide.

Results

Neither the mean AUC0−∞(geometric mean ratio: 1.01; 95% CI: 0.93–1.1,P = 0.88) nor the meanCmax(geometric mean ratio: 1.05; 95% CI: 0.94–1.2,P = 0.35) of repaglinide were statistically significantly different in the group carrying theCYP2C8*3mutant allele compared with wild‐types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3‐hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75–0.87,P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC0−∞of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04–1.2,P = 0.0048), but had no statistically significant effect on thet1/2. There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg.

Conclusions

The pharmacokinetics of repaglinide in subjects carrying theCYP2C8*3mutant allele did not differ significantly from those in the wild‐types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.
Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation
Authors: Brunner M. , Ziegler S. , Di Stefano A. F. D. , Dehghanyar P. , Kletter K. , Tschurlovits M. , Villa R. , Bozzella R. , Celasco G. , Moro L. , Rusca A. , Dudczak R. , Müller M.
Published: December 2005

Aims

The aims of the study were to: (1) evaluate the gastrointestinal transit, release and absorption of budesonide from tablets with a new multimatrix formulation (MMX®) designed to release the drug throughout the whole colon, and (2) assess the influence of food on budesonide bioavailability.

Methods

Two phase I studies, each comprising 12 healthy males, were performed. Gastrointestinal transit of 153Sm‐labelled tablets containing 9 mg budesonide was evaluated by means of pharmaco‐scintigraphy. The effect of food was tested by comparing plasma pharmacokinetics after intake of a high fat and high calorie breakfast with fasting controls.

Results

153Sm‐labelled tablets reached the ascending colon after a mean ± SD 9.8 ± 6.9 h. Initial tablet disintegration was observed in the ileum in 42% and the ascending and transverse colon in 33% of subjects. Ninety‐six per cent of the dose was absorbed into the systemic circulation during passage through the whole colon including the sigmoid. Food significantly decreased Cmax values from 1429 ± 1014 to 1040 ± 601 pg mL−1 (P = 0.028) and AUC values from 14 814 ± 11 254 to 13 486 ± 9369 pg h−1 mL−1 (P = 0.008). Mean residence time and tmax increased by 12–29%. There was no drug accumulation after 1 week of once daily oral administration of budesomide.

Conclusions

MMX®‐budesonide tablets appear suitable for targeted colonic drug delivery. Transit parameters and low systemic bioavailability warrant further studies with the new formulation.
Grassland yield declined by a quarter in 5 years of free‐air ozone fumigation
Authors: VOLK MATTHIAS , BUNGENER PATRICK , CONTAT FRANÇOIS , MONTANI MYRTA , FUHRER JÜRG
Published: December 2005

The sensitivity of seminatural grasslands to ozone (O3) pollution is not well known, in spite of the important function of these common ecosystems for agriculture and nature conservation. A 5‐year field experiment was carried out at a rural, mid‐elevation site at Le Mouret (Switzerland) to investigate the effect of elevated O3 on yield and species composition of a permanent, extensively managed, species‐rich old pasture. Using a free‐air fumigation system, circular plots of 7 m diameter were exposed to either ambient air (control plots) or to air containing O3 of approximately 1.5 × ambient concentrations. The resulting accumulated O3 exposure over the threshold of 40 ppb for one season ranged from 13.3 to 59.5 ppm h in the elevated O3 plots, and from 1.0 to 20.7 ppm h in the control plots. Subplots in each ring were harvested three times each year, and harvested biomass was separated into functional groups (FGs) (grasses, legumes, forbs). Productivity in both treatments decreased over time, but the yield of O3‐exposed plots decreased faster than that of the control plots, with the reduction being twice as large by the end of the fifth season. Compared with the ambient air control, loss in annual dry matter yield was 23% after 5 years. The change in annual biomass production because of O3 stress was accompanied by a change in the fractions of FGs, with the legume fraction showing a strong negative response. Such long‐term effects of O3 stress could have negative implications for the maintenance of biological diversity in rural landscapes across large areas of Europe. The results from this first long‐term experiment show that a moderately elevated O3 level reduces the productivity of intact grasslands during a 5‐year exposure under real field conditions.
The effects of maternal exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin on testicular steroidogenesis in infantile male rats
Authors: HAAVISTO T. E. , MYLLYMÄKI S. A. , ADAMSSON N. A. , BROKKEN L. J. S. , VILUKSELA M. , TOPPARI J. , PARANKO J.
Published: December 2005

Exposure of adult male animals to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) decreases serum androgen concentrations. Reduction in androgen levels after maternal exposure has also been reported, but these results have not been reproduced. We have earlier shown that TCDD stimulates rather than inhibits testosterone synthesis in the prenatal rat testis. The aim of the present study was to elucidate in utero‐induced effects of TCDD on testicular steroidogenesis in the 14‐day‐old infant rats. At that time the foetal Leydig cell population is still the prevailing source of androgens. Pregnant Sprague–Dawley dams were given a single oral dose of TCDD (0, 0.04, 0.2, or 1.0 μg/kg) on day 13 of pregnancy. On postnatal day 14, the body weight of male offspring was reduced after exposure to 1.0 μg/kg TCDD (from 33.9 ± 1.66 g to 31.6 ± 2.67 g). Relative testis weight, plasma testosterone, luteinizing hormone and follicle‐stimulating hormone levels remained unaltered in all exposure groups. Moreover, in ex vivo incubations, testosterone and cAMP production was not affected. StAR protein level in the freshly isolated testes was increased in the 0.2 μg/kg group, and seminiferous cord diameter in the 0.04 μg/kg group. The present study confirms our earlier findings in in utero TCDD‐exposed foetal testis indicating that maternal TCDD exposure does not negatively influence the developmental testosterone production of foetal type Leydig cells in rats.
Prochloraz: an imidazole fungicide with multiple mechanisms of action
Authors: VINGGAARD ANNE MARIE , HASS ULLA , DALGAARD MAJKEN , ANDERSEN HELLE RAUN , BONEFELD‐JØRGENSEN EVA , CHRISTIANSEN SOFIE , LAIER PETER , POULSEN METTE ERECIUS
Published: December 2005

Prochloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America within gardening and agriculture. Screening studies have shown that prochloraz elicits multiple mechanisms of action in vitro, as it antagonizes the androgen and the oestrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts as an antiandrogen in the Hershberger assay by reducing weights of reproductive organs, affecting androgen‐regulated gene expressions in the prostate and increasing luteinizing hormone levels. In order to investigate the developmental effects of prochloraz, pregnant Wistar dams were dosed perinatally with 30 mg/kg prochloraz. Results showed that prochloraz significantly reduced plasma and testicular testosterone levels in gestational day 21 male foetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. In male pups a significant increase in nipple retention was found, and the weight of the bulbourethral glands was decreased. Behavioural studies showed that the activity level and sweet preference of adult males were significantly increased, indicating that exposure during gestation and lactation causes permanent effects in adulthood. Overall, these results indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis. Thus, a novel endocrine disruptor has been identified that is mechanistically interesting as it elicits dual mechanisms of action and acts as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. That a fungicide with such effects is so widely used is a cause for concern, and its use should be reduced, thereby minimizing the risk of human exposure.
Bio‐social determinants of fertility
Authors: KOHLER HANS‐PETER , RODGERS JOSEPH LEE , MILLER WARREN B. , SKYTTHE AXEL , CHRISTENSEN KAARE
Published: December 2005

This paper reviews several studies that investigated the potential role of genetic factors in determining fertility outcomes. Our review demonstrates convincingly that fertility contains genetic variance; that is, differences between humans in their genetic make‐up affects their fertility outcomes and fertility‐related behaviours. This finding is robust using both heritabilities and coefficients of genetic variation, and using both direct measures of fertility outcomes and also fertility precursors like fecundity, marriage, fertility expectations and attempts to get pregnant (proception). Moreover, genetic variance can change over short periods of time or across educational levels, specifically for females, and the relevance of genetic variance seems to increase during times of increasing reproductive choice.
Examining intention to control preschool children's sugar snacking: a study of carers in Uganda
Authors: ÅSTRØM A. N. , KIWANUKA S. N.
Published: December 2005

Summary. Aim. The aims of this study were to investigate parents’ intention to control their children's sugar consumption and whether that behaviour is reported to occur in 3–5‐year‐old preschool children according to sociodemographics and attitudinal factors derived from the Theory of Planned Behaviour (TPB).

Design. Some 589 children aged 3–5 years (51% boys, response rate = 85%) attending nursery schools in Kampala Central (urban) and Nakawa (suburban), Uganda, were examined clinically for dental caries. A questionnaire to assess sociodemographic factors, sugar intake and the constructs of the TPB was completed by their parents’/caregivers in face‐to‐face interviews.

Results.  Analyses of variance revealed more positive attitudes and stronger intention to control children's intake of sugared snacks in highly as compared to less highly educated parents. Independent of educational level, parents having children with caries perceived themselves to have less control over their child’ intake of sugared snacks and perceived them to be more susceptible to tooth decay compared to parents of children without caries. In multiple linear regression, the TPB provided a significant prediction of intention with attitude (b = 0·16, P < 0·001), subjective norms (b = 0·18, P < 0·001) and perceived barriers (b = 0·11, P = 0·01), significant and reported sugar intake with attitudes (b = −0·10, P = 0·02), and perceived susceptibility (b = 16, P < 0·001) all significant.

Conclusion.  The TPB components predict parental intention to control sugar snacking and whether that behaviour occurs in preschool children. The strengths of parents’ attitudes and reported level of child sugar snacking varied between diverse socioeconomic family groups. Implications for oral health education are discussed.
Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric bipolar disorder
Authors: Frazier Jean A , Breeze Janis L , Makris Nikos , Giuliano Anthony S , Herbert Martha R , Seidman Larry , Biederman Joseph , Hodge Steven M , Dieterich Megan E , Gerstein Emily D , Kennedy David N , Rauch Scott L , Cohen Bruce M , Caviness Verne S
Published: December 2005

Objective:  Few magnetic resonance imaging (MRI) studies of bipolar disorder (BPD) have investigated the entire cerebral cortex. Cortical gray matter (GM) volume deficits have been reported in some studies of adults with BPD; this study assessed the presence of such deficits in children with BPD.

Methods:  Thirty‐two youths with DSM‐IV BPD (mean age 11.2 ± 2.8 years) and 15 healthy controls (HC) (11.2 ± 3.0 years) had structured and clinical interviews, neurological examinations, neurocognitive testing, and MRI scanning on a 1.5 T GE Scanner. Image parcellation divided the neocortex into 48 gyral‐based units per hemisphere, and these units were combined into frontal (FL), temporal (TL), parietal (PL), and occipital (OL) lobe volumes. Volumetric differences were examined using univariate linear regression models with α = 0.05.

Results:  Relative to controls, the BPD youth had significantly smaller bilateral PL, and left TL. Analysis of PL and TL gyri showed significantly smaller volume in bilateral postcentral gyrus, and in left superior temporal and fusiform gyri, while the parahippocampal gyri were bilaterally increased in the BPD group. Although the FL overall did not differ between groups, an exploratory analysis showed that the right middle frontal gyrus was also significantly smaller in the BPD group.

Conclusions:  Children with BPD showed deficits in PL and TL cortical GM. Further analyses of the PL and TL found differences in areas involved in attentional control, facial recognition, and verbal and declarative memory. These cortical deficits may reflect early age of illness onset.
Are the arginine vasopressin V1a receptor microsatellites related to hypersexuality in children with a prepubertal and early adolescent bipolar disorder phenotype?
Authors: Geller Barbara , Tillman Rebecca , Badner Judith A , Cook Edwin H
Published: December 2005

Objective:  To examine family‐based transmission of the number of 5′ flanking arginine vasopressin V1a receptor (AVPR1A) microsatellites, which include [(GATA)14] and complex [(CT)4‐TT‐(CT)8‐(GT)24] repeats, in probands with a prepubertal and early adolescent bipolar disorder phenotype (PEA‐BP). Preferential transmission of the number of AVPR1A microsatellite repeats to hypersexual and uninhibited people‐seeking probands was hypothesized, based on reports from preclinical work in the literature.

Methods:  Probands were 83 participants in an ongoing controlled study of PEA‐BP. The PEA‐BP phenotype was defined by DSM‐IV mania with at least one of the cardinal symptoms of mania (elation and/or grandiosity) to avoid diagnosing mania only by symptoms that overlapped with those for attention‐deficit hyperactivity disorder (ADHD). Comprehensive assessment of the probands included separate Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH‐U‐KSADS) interviews of parents about their children and of children about themselves. Hypersexuality and uninhibited people‐seeking were assessed from the corresponding WASH‐U‐KSADS items. Microsatellite genotyping of the AVPR1A repeats was conducted using fluorescently labeled primers and detected by laser‐induced fluorescence. Alleles were determined with the assistance of semi‐automated allele‐calling software. There were 32 complete, biological trios (28 informative families) for the GATA repeat and 34 complete, biological trios (30 informative families) for the complex repeat. Data were analyzed using case–control and family‐based association methods.

Results:  Preferential transmission of AVPR1A GATA or complex repeats was not significant for hypersexuality or uninhibited people‐seeking, using the transmission disequilibrium test. Similarly, case–control analyses found no significant associations between hypersexuality or uninhibited people‐seeking and the number of AVPR1A GATA or complex repeats. For p < 0.05, there was about 80% power to detect odds ratios of 5.0 and 4.0 (in the family‐based analyses) and 3.5 and 2.6 (in the case–control analyses), for allele frequencies of 0.1 and 0.5, respectively.

Conclusion:  Preferential transmission of AVPR1A to hypersexual or uninhibited people‐seeking probands was not supported.
Review and meta‐analysis of the phenomenology and clinical characteristics of mania in children and adolescents
Authors: Kowatch Robert A , Youngstrom Eric A , Danielyan Arman , Findling Robert L
Published: December 2005

Objective:  Using predetermined criteria for study quality and methods, a literature review and meta‐analysis of seven reports about pediatric bipolar disorder (BPD) was conducted to determine if there is a consistent picture of the phenomenology and clinical characteristics of BPD in children and adolescents.

Methods:  Searches were conducted in MedLine and PsycINFO using the terms mania, BPD, children and adolescents, and was limited to published articles in peer‐reviewed journals. Seven reports were selected that met the following criteria: a systematic method for the elicitation and reporting of symptoms and clinical characteristics of subjects; subjects were interviewed by a trained researcher or clinician; ages 5–18 years; use of a diagnostic system, either DSM or RDC for categorization; a consensus method for the establishment of the diagnosis of BPD.

Results:  Most DSM‐IV symptoms of mania were common in the children and adolescents with BPD with the most common symptoms being increased energy, distractibility, and pressured speech. On average, four of five bipolar cases also showed threshold levels of irritable mood and grandiosity, and more than 70% of all cases showed elated/euphoric mood, decreased need for sleep, or racing thoughts. Roughly 69% of cases also showed poor judgment, whereas only half of bipolar cases demonstrated flight of ideas, and slightly more than one‐third showed hypersexuality or psychotic features.

Conclusions:  The clinical picture that emerges is that of children or adolescents with periods of increased energy (mania or hypomania), accompanied by distractibility, pressured speech, irritability, grandiosity, racing thoughts, decreased need for sleep and euphoria/elation.
Preliminary evidence for persistent abnormalities in amygdala volumes in adolescents and young adults with bipolar disorder
Authors: Blumberg Hilary P , Fredericks Carolyn , Wang Fei , Kalmar Jessica H , Spencer Linda , Papademetris Xenophon , Pittman Brian , Martin Andres , Peterson Bradley S , Fulbright Robert K , Krystal John H
Published: December 2005

Objectives:  Abnormalities in volumes of the amygdala have been reported previously in adolescents and adults with bipolar disorder (BD). Several studies have reported reduced volumes in adolescents with BD; however, both decreases and increases in volumes have been reported in adults with BD. Understanding of potential developmental contributions to these disturbances in morphology of the amygdala has been limited by the absence of longitudinal data in persons with BD. Here we use a within‐subject longitudinal design to investigate whether amygdala volume abnormalities persist in adolescents and young adults with BD over a time interval of approximately 2 years.

Methods:  Participants included 18 adolescents and young adults: 10 participants with BD I and 8 healthy comparison participants. Amygdala volumes were measured on high‐resolution magnetic resonance imaging scans acquired twice for each subject over intervals of approximately 2 years. Amygdala volumes were the dependent measures in a mixed‐model statistical analysis to compare amygdala volumes between groups over time while covarying for total brain volume.

Results:  Amygdala volumes were significantly smaller in adolescents and young adults with BD compared with healthy participants (p = 0.018). The effect of time was not significant.

Conclusions:  Although the sample size is modest, this study provides preliminary evidence to support the presence of decreased amygdala volumes in adolescents and young adults with BD that persist during this developmental epoch.
Using affect‐modulated startle to study phenotypes of pediatric bipolar disorder
Authors: Rich Brendan A , Bhangoo Robinder K , Vinton Deborah T , Berghorst Lisa H , Dickstein Daniel P , Grillon Christian , Davidson Richard J , Leibenluft Ellen
Published: December 2005

Objectives:  Affective neuroscience research that investigates core symptoms of pediatric bipolar disorder (PBD) may be effective in differentiating PBD phenotypes. The current study used affect‐modulated startle to examine potential differences in reactivity to emotional stimuli (reward and punishment) in narrow and broad phenotype PBD and controls.

Methods:  Thirty children meeting DSM‐IV bipolar disorder criteria (i.e. narrow phenotype PBD with defined manic episodes with elevated/expansive mood), 19 children meeting criteria for severe mood dysregulation (i.e. broad phenotype with chronic irritability, hyper‐reactivity, and hyperarousal), and 19 controls completed a lottery startle paradigm involving reward (money) and punishment (loud noise). Startle probes were presented during anticipation of the emotional stimulus, immediately following the presentation of the stimulus, or during return to baseline following the stimulus.

Results:  By self‐report, patients and controls found the putative punishment to be preferable to the neutral condition. In the reward condition, patient samples reported greater arousal than did controls, but no between‐group differences were found on the magnitude of startle response during the reward, punishment, or neutral conditions.

Conclusions:  The failure to find differences in affect‐modulated startle between control children and those with narrow or broad PBD phenotypes speaks to the methodological challenges associated with studying reward mechanisms in PBD. Alternative paradigms that focus on different aspects of reward mechanisms are discussed.
N‐acetylaspartate levels in bipolar offspring with and at high‐risk for bipolar disorder
Authors: Gallelli Kim A , Wagner Christopher M , Karchemskiy Asya , Howe Meghan , Spielman Daniel , Reiss Allan , Chang Kiki D
Published: December 2005

Objectives:  Studies have reported decreased N‐acetylaspartate (NAA) in dorsolateral prefrontal cortex (DLPFC) of adults and children with bipolar disorder (BD), suggesting decreased neuronal density in this area. However, it is unclear if this finding represents neurodegeneration after or a trait marker present before BD onset. To address this question, we used proton magnetic resonance spectroscopy (1H‐MRS) to compare DLPFC levels of NAA among bipolar offspring with early‐onset BD, bipolar offspring with subsyndromal symptoms of BD and healthy children.

Methods:  Participants were 9–18 years old, and included 60 offspring of parents with bipolar I or II disorder (32 with BD and 28 with subsyndromal symptoms of BD), and 26 healthy controls. 1H‐MRS at 3 T was used to study 8‐cm3 voxels placed in left and right DLPFC.

Results:  There were no significant group differences in mean right or left DLPFC NAA/Cr ratios. Exploratory analyses of additional metabolites (myoinositol, choline) also yielded no significant group differences. NAA/Cr ratios were not correlated with age, duration of illness, or exposure to lithium or valproate.

Conclusions:  Our findings suggest that DLPFC NAA/Cr ratios cannot be used as a trait marker for BD. Although we did not find decreased DLPFC NAA/Cr ratios in children and adolescents with BD, it is still possible that such levels begin to decrease after longer durations of illness into adulthood. Longitudinal neuroimaging studies of patients with BD accounting for developmental and treatment factors are needed to further clarify the neurodegenerative aspects of BD.
Family, twin, adoption, and molecular genetic studies of juvenile bipolar disorder
Authors: Althoff Robert R , Faraone Stephen V , Rettew David C , Morley Christopher P , Hudziak James J
Published: December 2005

Juvenile bipolar disorder (JBD) has been a subject of significant research and debate. Phenotypic differences between JBD and adult‐onset bipolar disorder have led researchers to question whether or not similar neuropathologic mechanisms will be found. While much is known about the genetic and environmental contributions to the adult‐onset phenotype, less is known about their contributions to JBD. Here, we review family, twin, adoption, and molecular genetic studies of JBD. Behavioral genetic data suggest both genetic and environmental contributions to JBD, while molecular genetic studies find linkage to age of onset of bipolar disorder to chromosomes 12p, 14q, and 15q. Additionally, changes associated with symptom age of onset have been recently reported in the brain‐derived neurotrophic factor (BDNF) and glycogen synthase kinase 3‐beta (GSK3‐beta) genes. We contend that further progress in discovering the precise genetic and environmental contributions to JBD may depend on advances in phenotypic refinement, an increased appreciation of comorbid conditions, and more investigation of the longitudinal course of the disorder.
Comparing diagnostic checklists for pediatric bipolar disorder in academic and community mental health settings
Authors: Youngstrom Eric , Meyers Oren , Demeter Christine , Youngstrom Jen , Morello Laura , Piiparinen Richard , Feeny Norah , Calabrese Joseph R , Findling Robert L
Published: December 2005

Objectives:  To compare six promising mania measures, the Parent Mood Disorder Questionnaire (P‐MDQ), the Adolescent self‐report MDQ, the 10‐item short form of the Parent General Behavior Inventory (PGBI‐SF10), the 28‐item Adolescent General Behavior Inventory (AGBI), the Parent Young Mania Rating Scale (P‐YMRS), and the adolescent YMRS, in a demographically diverse outpatient sample.

Methods:  Participants were 262 outpatients (including 164 males and 131 African‐Americans) presenting to either an academic medical center (n = 153) or a community mental health center (n = 109). Diagnoses were based on semi‐structured interviews with the parent and then youth sequentially.

Results:  Ninety youths (34%) met criteria for a bipolar spectrum disorder. Parent measures yielded Areas Under the Receiver Operating Curve (AUROC) values of 0.81 for the PGBI‐SF10 to 0.66 for the P‐YMRS. Adolescent report measures performed significantly less well, with AUROCs ranging from 0.65 to 0.50. There were no significant differences in the diagnostic performance of the measures across the sites or by racial groups, although the reliability of measures tended to be lower in the urban community mental health site. The PGBI‐SF10 made a significant contribution to logistic regression models examining all combinations of the instruments. The P‐MDQ added information in the younger age group, and no measure improved classification of bipolar cases after controlling for the PGBI‐SF10 in the older age group.

Discussion:  Results replicate previous findings that, in decreasing order of efficiency, the PGBI‐SF10, P‐MDQ, and P‐YMRS significantly discriminate bipolar from non‐bipolar cases in youths aged 5–18; and they appear robust in a demographically diverse community setting. Adolescent self‐report measures are significantly less efficient, sometimes performing no better than chance at detecting bipolar cases.
Family environment in families with versus families without parental bipolar disorder: a preliminary comparison study
Authors: Romero Soledad , DelBello Melissa P , Soutullo Cesar A , Stanford Kevin , Strakowski Stephen M
Published: December 2005

Objectives:  To compare family environmental characteristics of families with at least one bipolar parent and families with parents without any Axis I disorder.

Methods:  Family environment of 24 families with at least one parent with bipolar disorder (BPD) and 27 families with healthy parents (healthy families, HF) were assessed using the Family Environment Scale (FES). We compared FES subscale scores between BPD and HF. We also compared FES normative scores with scores of BPD families.

Results:  Seventeen (71%) of the 24 BPD families had at least one child with a mood disorder and one (3.7%) of the 27 HF had a child with a mood disorder. Families with BPD reported lower cohesion (p = 0.009) and expressiveness (p = 0.03) scores compared with HF, after controlling for group socioeconomic status differences. Bilineal BPD families had higher cohesion scores than unilineal BPD families (p = 0.05). We found no significant differences in any subscales between BPD families with (n = 9) versus without (n = 15) children with BPD. Compared with normative FES data BPD families reported lower cohesion (C) (p = 0.02) and independence (IND) (p = 0.004) scores and higher conflict (CON) (p = 0.02), intellectual‐cultural orientation (ICO) (p = 0.05), moral‐religious emphasis (MRE) (p < 0.001) and control (CTL) (p < 0.001) scores.

Conclusion:  Our results suggest that members of BPD families may have difficulty communicating effectively with one another, suggesting that interventions aimed at improving this may be beneficial to patients with BPD. Results suggest that the impact of different lifestyles in different communities may influence FES scores, and thus it is important to use demographically matched comparison groups.
The CBCL predicts DSM bipolar disorder in children: a receiver operating characteristic curve analysis
Authors: Faraone Stephen V , Althoff Robert R , Hudziak James J , Monuteaux Michael , Biederman Joseph
Published: December 2005

Background:  No clear consensus has been reached yet on how best to characterize children who suffer from pediatric bipolar disorder (PBD). The CBCL‐PBD profile on the Child Behavior Checklist (CBCL) has been consistently reported showing deviant findings on the Attention Problems, Aggressive Behavior, and Anxious‐Depressed subscales.

Aim:  To examine the sensitivity and specificity of the proposed CBCL‐PBD profile for determining DSM diagnosis of PBD.

Methods:  We applied receiver operating characteristic (ROC) curve analysis to data from 471 probands from two family studies of attention‐deficit hyperactivity disorder and their 410 siblings.

Results:  The CBCL‐PBD score demonstrated an area under the curve (AUC) of 0.97 for probands and 0.82 for siblings for current diagnosis of PBD, suggesting that the CBCL‐PBD provided a highly efficient way of identifying subjects with a current diagnosis of PBD in this sample.

Conclusions:  These findings suggest that the CBCL‐PBD may provide a highly efficient way of screening for childhood bipolar disorder.
Molecular evolution of the avian growth hormone gene and comparison with its mammalian counterpart
Authors: Buggiotti L. , Primmer C. R.
Published: December 2005

The molecular evolution of all available avian growth hormone (GH) gene sequences was investigated using both maximum-likelihood and parsimony methods, and the patterns compared to those found in mammals. In contrast to the rapid bursts of evolution observed for mammalian GH, the evolutionary rate of the avian GH mature peptide appears to have been more constant. However several positively selected sites were identified at functionally important positions in the avian signal peptide by the site-specific likelihood method. This implies that sequence variation in the avian GH signal peptide may be adaptive, although more conservative parsimony methods failed to confirm this. Nevertheless, the differing patterns of avian and mammalian GH signal peptide molecular evolution are consistent with the apparently differing roles of GH in controlling growth in these taxonomic groups and support the hypothesis that signal peptide sequence variation may in fact be the basis for increased functional complexity.
Premotor neuronal plasticity in monkeys adapting to a new dynamic environment
Authors: Xiao Jun
Published: December 2005

Recent evidence indicates that premotor cortex (PM) in addition to their well‐established motor functions, also play a role in nonmotor processes such as spatial attention and working memory. In the present study, neuronal activities in dorsal PM (PMd) and ventral PM (PMv) were recorded in a force field adaptation task. This study found that PM neurons show learning‐related plasticity and that a neuron demonstrates either one type or multiple types of properties (i.e. kinematic, dynamic, and memory). The current study reveals that memory properties could be displayed by one or a combination of the cell activity parameters [i.e. average firing rate (AFR), dynamic range (DR), and preferred direction (PD)]. A predominant percentage of cells displayed memory properties with AFR or AFR plus other parameters. This study investigated the memory properties vs. the time sequence of the task trial [i.e. delay time (DT), movement time (MT), and target holding time (THT)] and found that: (i) most neurons display memory properties only in one time window; (ii) few neurons display memory properties in three time windows, and (iii) there are significantly more cells showing memory properties during MT than during any other time windows. There are cells that show memory I (changing their tuning curves in the force field and retaining those changes after the force field was removed), memory II (changing their tuning curves after the force field was removed), or both properties. Significantly more cells display one type of memory property (memory I or memory II) rather than both types of memory properties (memory I and memory II).
Striatal muscarinic receptor antagonism reduces 24‐h food intake in association with decreased preproenkephalin gene expression
Authors: Pratt Wayne E. , Kelley Ann E.
Published: December 2005

Cholinergic interneurons of the striatum respond to motivationally relevant stimuli and are involved in appetitive learning. However, there has been relatively little inquiry into the role of striatal acetylcholine in food motivation. Here we show in rats that a single infusion of the muscarinic receptor antagonist scopolamine (0, 5.0 or 10.0 µg/0.5 µL bilaterally) potently reduced 24‐h food intake following injections into either the ventral or dorsal striatum, without affecting water intake. Furthermore, muscarinic receptor blockade induced reliable and widespread reductions in striatal preproenkephalin, but not preprodynorphin, mRNA expression. These data suggest a novel role for striatal acetylcholine in modulating feeding behavior via its effects on enkephalin gene expression. As prior research indicates a critical role for striatal enkephalin in consummatory behaviors and palatability, we hypothesize that cholinergic interneurons assist in translating hypothalamic energy state signals into food‐directed behaviors via their regulation of striatal opioid peptides.
Local activation of the nitric oxide/cyclic guanosine monophosphate pathway in growth cones regulates filopodial length via protein kinase G, cyclic ADP ribose and intracellular Ca2+ release
Authors: Welshhans Kristy , Rehder Vincent
Published: December 2005

Nitric oxide (NO) is a gaseous messenger that has been shown to affect growth cone motility and neurite outgrowth in several model systems, but how NO brings about its effects is not understood. We have previously demonstrated that global and long‐term application of NO to Helisoma trivolvis B5 neurons results in a transient increase in filopodial length, decrease in filopodial number and decrease in neurite outgrowth, all of which are mediated via soluble guanylyl cyclase (sGC) and involve an increase in the intracellular Ca2+ concentration [S. Van Wagenen & V. Rehder (1999)Journal of Neurobiology, 39, 168–185; K.R. Trimm & V. Rehder (2004)European Journal of Neuroscience, 19, 809–818]. The goal of the current study was twofold: to investigate the effects of short‐term NO exposure on individual growth cones and to further elucidate the downstream pathway through which NO exerts its effects. Local application of the NO donor NOC‐7 for 10–20 ms via puffer micropipette resulted in a transient increase in filopodial length and a small decrease in filopodial number. We show evidence that these effects of NO are mediated via sGC, protein kinase G and cyclic ADP ribose, resulting in the release of Ca2+ from intracellular stores, probably of the ryanodine‐sensitive type. These results suggest that growth cones expressing sGC are highly sensitive to local and short‐term exposure to NO, which they may experience during pathfinding, and that the stereotyped response of transient filopodial elongation seen in B5 neurons in response to NO requires intracellular Ca2+ release.
Suppression of fibrous scarring in spinal cord injury of rat promotes long‐distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery
Authors: Klapka Nicole , Hermanns Susanne , Straten Guido , Masanneck Carmen , Duis Simone , Hamers Frank P. T. , Müller Daniela , Zuschratter Werner , Müller Hans Werner
Published: December 2005

Traumatic injury of the central nervous system results in formation of a collagenous basement membrane‐rich fibrous scar in the lesion centre. Due to accumulation of numerous axon‐growth inhibitory molecules the lesion scar is considered a major impediment for axon regeneration. Following transection of the dorsal corticospinal tract (CST) at thoracic level 8 in adult rats, transient suppression of collagenous scarring in the lesion zone by local application of a potent iron chelator and cyclic adenosine monophosphate resulted in the delay of fibrous scarring. Treated animals displayed long‐distance growth of CST axons through the lesion area extending for up to 1.5–2 cm into the distal cord. In addition, the treatment showed a strong neuroprotective effect, rescuing cortical motoneurons projecting into the CST that normally die (30%) after thoracic axotomy. Further, anterogradely traced CST axons regenerated through both grey and white matter and developed terminal arborizations in grey matter regions. In contrast to controls, injured animals receiving treatment showed significant functional recovery in the open field, in the horizontal ladder and in CatWalk locomotor tasks. We conclude that the fibrous lesion scar plays a pivotal role as a growth barrier for regenerating axons in adult spinal cord and that a delay in fibrotic scarring by local inhibition of collagen biosynthesis and basement membrane deposition is a promising and unique therapeutic strategy for treating human spinal trauma.
A population‐based model of the nonlinear dynamics of the thalamocortical feedback network displays intrinsic oscillations in the spindling (7–14 Hz) range
Authors: Yousif Nada A. B. , Denham Michael
Published: December 2005

The thalamocortical network is modelled using the Wilson–Cowan equations for neuronal population activity. We show that this population model with biologically derived parameters possesses intrinsic nonlinear oscillatory dynamics, and that the frequency of oscillation lies within the spindle range. Spindle oscillations are an early sleep oscillation characterized by high‐frequency bursts of action potentials followed by a period of quiescence, at a frequency of 7–14 Hz. Spindles are generally regarded as being generated by intrathalamic circuitry, as decorticated thalamic slices and the isolated thalamic reticular nucleus exhibit spindles. However, the role of cortical feedback has been shown to regulate and synchronize the oscillation. Previous modelling studies have mainly used conductance‐based models and hence the mechanism relied upon the inclusion of ionic currents, particularly the T‐type calcium current. Here we demonstrate that spindle‐frequency oscillatory activity can also arise from the nonlinear dynamics of the thalamocortical circuit, and we use bifurcation analysis to examine the robustness of this oscillation in terms of the functional range of the parameters used in the model. The results suggest that the thalamocortical circuit has intrinsic nonlinear population dynamics which are capable of providing robust support for oscillatory activity within the frequency range of spindle oscillations.
Effects of systemically administered cocaine on sensory responses to peri‐threshold vibrissae stimulation: individual cells, ensemble activity, and animal behaviour
Authors: Rutter John J. , Devilbiss David M. , Waterhouse Barry D.
Published: December 2005

Previous studies have shown that systemic administration of cocaine transiently alters stimulus‐evoked responses of ventral posteromedial (VPM) thalamic neurons. Results from these single‐unit electrophysiological studies revealed that cocaine was equally likely to augment or attenuate the magnitude of sensory evoked responses following threshold level stimulation of peripheral receptive fields. In an attempt to clarify the impact of cocaine administration on sensory signal processing, we examined the drug's effects on responses of individual neurons and ensembles of VPM thalamic neurons to sensory stimuli, and performance of subjects in a sensory detection behavioural task. Extracellular responses of single (n = 1 cell/rat) or multiple VPM thalamic neurons (n = 10–40 cells/rat) were monitored before and after cumulative doses of cocaine (0.25–2.0 mg/kg i.v.). Neuronal responses were characterized by assessing the response profile to a range of peri‐threshold‐level deflections of the optimal whisker on the contralateral face. Drug effects on stimulus‐response curves, determined from quantitative analysis of spike train data, indicated that whereas cocaine elicits variable effects at the single cell level, the stimulus‐evoked response of the recorded population was likely to increase following lower (0.25–1.0 mg/kg i.v.) doses of cocaine. Furthermore, cocaine preferentially enhanced responses to smaller magnitude deflections of vibrissa, altering the response profile from a mode that accurately conveyed stimulus strength to one that increased detection at the expense of discrimination. Finally, a similar pattern emerged in a behavioural paradigm involving rats trained to detect variable amplitude whisker pad stimulation, suggesting a common action of cocaine that may contribute to the drug's addictive properties.