bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between serum TSH, free T4 and serum liver enzyme activities in a large cohort of unselected outpatients
Authors: Targher Giovanni , Montagnana Martina , Salvagno Gianluca , Moghetti Paolo , Zoppini Giacomo , Muggeo Michele , Lippi Giuseppe
Published: September 2010

Objective  Although overt thyroid dysfunction is associated with some liver abnormalities, there is a dearth of information on liver function tests across thyroid function tests. We assessed the relationship between serum liver enzyme activity and thyroid function tests in a cohort of adult individuals.

Design, patients and measurements  We performed a retrospective analysis on the database of the Clinical Chemistry Laboratory at the Verona University Hospital to retrieve results of serum liver enzyme activities [alanine aminotransferase (ALT), γ‐glutamyltransferase (GGT)] and thyroid function tests (TSH and free T4), which have been performed on the whole cohort of outpatient adults consecutively referred by general practitioners for routine blood testing during the last 3 years.

Results  Cumulative results for serum GGT, ALT and TSH concentrations were retrieved for 10 292 (68·3% females) outpatient adults with a wide range of age and thyroid function tests. Subjects were categorized according to serum TSH concentrations as follows: < 0·1, 0·1–0·35, 0·36–4·5, 4·6–10 and >10 mU/l. Serum GGT and ALT concentrations increased steadily across the increasing TSH categories (P < 0·0001 for trends), ranging from mean values of 36 to 62 U/l for GGT and from 29 to 41 U/l for ALT, respectively. Similarly, there was a negative, graded, relationship between serum GGT and ALT concentrations and free T4 categories. The results did not change after adjusting for gender, age, lipids and fasting glucose concentrations.

Conclusions   Our findings suggest that hypothyroidism and thyroid function tests, even within the reference range, are associated with slightly increased serum GGT and ALT activity concentrations.
Effects of environmental stress cascade up through four trophic levels in a salt marsh study system
Authors: MOON DANIEL C. , MOON JAMIE C.
Published: September 2010

1. Although in recent years there have been a number of studies demonstrating trophic cascades in terrestrial systems, it is still unclear what environmental conditions enable or enhance such cascades, especially among four trophic levels.

2. In this study, the influence of environmental stress (increased soil pore water salinity) on a four trophic level study system in a Florida salt marsh was examined by experimentally increasing soil pore water salinity. Effects of increased salinity on the quality of the host plant, Batis maritima, were assessed, as were resulting effects on the lepidopteran herbivore Ascia monuste, and the primary parasitoids and hyperparasitoids of its caterpillars.

3. Increased salinity altered host‐plant quality, which subsequently affected the consumer species. These effects of altered plant quality cascaded up through the herbivore and primary parasitoid to the hyperparasitoid Hypopteromalus inimicus, influencing its density, sex ratio, body size, and initial egg load.

4. These results demonstrate how heterogeneity in environmental stress can result in effects that cascade up through four trophic levels. We suggest that such strong effects at higher trophic levels may be more likely in systems in which relationships are more specific and intimate such as those among hosts, parasitoids, and hyperparasitoids.
Analytical decision model for sample size and effectiveness projections for use in planning a population‐based randomized controlled trial of colorectal cancer screening
Authors: Chiu Sherry Y‐H , Malila Nea , Yen Amy M‐F , Anttila Ahti , Hakama Matti , Chen H‐H
Published: September 2010

Rationale, aims and objectives  Population‐based randomized controlled trials (RCTs) often involve enormous costs and long‐term follow‐up to evaluate primary end points. Analytical decision‐simulated model for sample size and effectiveness projections based on primary and surrogate end points are necessary before planning a population‐based RCT.

Method  Based on the study design similar to two previous RCTs, transition rates were estimated using a five‐state natural history model [normal, preclinical detection phase (PCDP) Dukes' A/B, PCDP Dukes' C/D, Clinical Dukes' A/B and Clinical Dukes' C/D]. The Markov cycle tree was assigned transition parameters, variables related to screening and survival rate that simulated results of 10‐year follow‐up in the absence of screening for a hypothetical cohort aged 45–74 years. The corresponding screened arm was to simulate the results after the introduction of population‐based screening for colorectal cancer with fecal occult blood test with stop screen design.

Results  The natural course of mean sojourn time for five‐state Markov model were estimated as 2.75 years for preclinical Dukes' A/B and 1.38 years for preclinical Dukes' C/D. The expected reductions in mortality and Dukes' C/D were 13% (95% confidence intervals: 7–19%) and 26% (95% confidence intervals: 20–32%), respectively, given a 70% acceptance rate and a 90% colonoscopy referral rate. Sample sizes required were 86 150 and 65 592 subjects for the primary end point and the surrogate end point, respectively, given an incidence rate up to 0.0020 per year.

Conclusions  The sample sizes required for primary and surrogate end points and the projection of effectiveness of fecal occult blood test for colorectal cancer screening were developed. Both are very important to plan a population‐based RCT.
Friction and shear highly associated with pressure ulcers of residents in long‐term care – Classification Tree Analysis (CHAID) of Braden items
Authors: Lahmann Nils A. , Tannen Antje , Dassen Theo , Kottner Jan
Published: September 2010

Aims  Among various risk assessment scales for the development of pressure ulcers in long‐term care residents that have been published in the last three decades, the Braden scale is among the most tested and applied tools. The sum score of the scale implies that all items are equally important. The aim of this study is to show whether specific items are of greater significance than others and therefore have a higher clinical relevance.

Design  Data analysis of six pressure ulcer prevalence studies (2004–2009).

Methods  A total of 17 666 residents (response rate 79.6%) in 234 long‐term care facilities participated in 6 annual point prevalence studies that were conducted from 2004 to 2009 throughout Germany. For the classification of the sample regarding pressure ulcers as a dependent variable and the Braden items as predictor variables, Chi‐square Automatic Interaction Detector (CHAID) for modelling classification trees has been used.

Results  Pressure ulcer prevalence was 5.4% including pressure ulcer grade 1 and 3.4% for pressure ulcer grades 2–4. CHAID analysis for the classification tree provided the item ‘friction and shear’ as the most important predictor for pressure ulcer prevalence. On the second level, the strongest predictors were ‘nutrition’ and ‘activity’ and on the third level they were ‘moisture’ and ‘mobility’. Residents with problems regarding ‘friction and shear’ and poor nutritional status present with an 18.0 (14.8) pressure ulcer prevalence which is 3–4 times higher than average.

Conclusion  CHAID analyses have shown that all items of the Braden scale are not equally important. For residents in long‐term care facilities in Germany, the existence of ‘friction and shear’ as a potential and especially as a manifest problem has had the strongest association with pressure ulcer prevalence.
Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies
Authors: Yatham Lakshmi N , Kennedy Sidney H , O'Donovan Claire , Parikh Sagar , MacQueen Glenda , McIntyre Roger , Sharma Verinder , Silverstone Peter , Alda Martin , Baruch Philippe , Beaulieu Serge , Daigneault Andree , Milev Roumen , Young L. Trevor , Ravindran Arun , Schaffer Ayal , Connolly Mary , Gorman Chris P
Published: September 2010

Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence‐based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first‐line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood‐stabilizing agents are first‐line treatments for bipolar depression. First‐line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring.
Outcome following a first manic episode: cross‐national US and Taiwan comparison
Authors: Strakowski Stephen M , Tsai Shang‐Ying , DelBello Melissa P , Chen Chiao‐Chicy , Fleck David E , Adler Caleb M , Arndt Stephan , Amicone Jennifer
Published: September 2010

Objectives:  Bipolar disorder (BD) is recognized as a significant psychiatric condition worldwide, yet little is known about cross‐national differences in the course of illness. This information might clarify features of the disorder that are illness versus culturally specific. Therefore, the aim of this study was to identify differential and shared outcome predictors in first‐episode manic bipolar patients in Cincinnati, OH, USA and Taipei, Taiwan.

Methods:  DSM‐IV bipolar patients were identified at the time of their first manic or mixed episode and were prospectively followed in a naturalistic, longitudinal study for one year. Patients were recruited from a first psychiatric hospitalization at university‐affiliated, urban hospitals in Taipei and Cincinnati. The primary outcome measures were remission, recovery, recurrence and percent of follow‐up spent with affective symptoms and syndromes. Treatment adherence was also assessed, as were a number of possible mediator variables.

Results:  The two patient groups showed a number of significant differences in index clinical presentation on characteristics previously associated with outcome in other studies (e.g., substance abuse). The patients in Taipei showed significantly better outcome on virtually all measures. Some of these findings reflected differences in index (mediator) variables, whereas others persisted after controlling for potential baseline confounds.

Conclusions:  The early course of BD varies between Chinese and American patients. Some of this variance results from demographic and clinical cross‐national differences in premorbid variables. Other sources of variance remain to be identified.
Brain systems underlying response flexibility in healthy and bipolar adolescents: an event‐related fMRI study
Authors: Nelson Eric E , Vinton Deborah T , Berghorst Lisa , Towbin Kenneth E , Hommer Rebecca E , Dickstein Daniel P , Rich Brendan A , Brotman Melissa A , Pine Daniel S , Leibenluft Ellen
Published: September 2010

Objectives:  Previous studies have indicated abnormalities in response flexibility in pediatric bipolar disorder (BD). Dysfunction in response flexibility may contribute to the pattern of behavioral and emotional dysregulation that is characteristic of BD, since depressed and manic patients respond inflexibly to emotional stimuli (i.e., anhedonia in the case of depression or inappropriate positive affect in the case of mania). The present study was undertaken to determine if neuronal responses differed between BD and control subjects on a simple motor response flexibility task.

Methods:  To elucidate the neural substrates mediating response flexibility in pediatric BD, we studied 25 youth with BD and 17 age‐, gender‐ and IQ‐matched controls (CON) as they performed the change task while undergoing event‐related functional magnetic resonance imaging (fMRI). The change task is a new fMRI task that requires subjects to both inhibit and replace a prepotent motor response with another motor response after the initial response has been cued.

Results:  On correctly performed change trials relative to correctly performed go trials, BD patients generated significantly more activity in the left dorsolateral prefrontal cortex (DLPFC) and in the primary motor cortex than did healthy controls, even though performance levels did not differ across groups.

Conclusions:  These results indicate that functional deficits within the left DLPFC may mediate deficits in response flexibility in pediatric BD. This deficit may extend beyond the realm of motor control and also affect emotion regulation.
The early manifestations of bipolar disorder: a longitudinal prospective study of the offspring of bipolar parents
Authors: Duffy Anne , Alda Martin , Crawford Leah , Milin Robert , Grof Paul
Published: September 2010

Objective:  A major aim of this longitudinal high‐risk study is to identify reliable early indicators of emerging bipolar disorder (BD) among offspring from well‐characterized parents.

Methods:  High‐risk offspring were recruited from families in which one parent had BD diagnosed on the basis of the Schedule for Affective Disorders and Schizophrenia – Lifetime version (SADS‐L) interviews and DSM‐IV diagnostic criteria and the other parent was well. Bipolar parents were further subdivided on the basis of response or non‐response to long‐term lithium. A comparison group of offspring was recruited from well parents diagnosed on the basis of either SADS‐L interviews or the family history method. All consenting offspring from high‐risk and control families were assessed longitudinally with the Schedule for Affective Disorders and Schizophrenia for School‐aged Children – Present and Lifetime version (KSADS‐PL) interviews and DSM‐IV diagnoses were made on a blind consensus review. The offspring were reassessed on average annually, as well as at any time symptoms developed.

Results:  Antecedent conditions to BD in both high‐risk groups included sleep and anxiety disorders, while attention‐deficit hyperactivity disorder and pre‐psychotic conditions were antecedents among the offspring of lithium non‐responders only. Among those offspring developing BD, the index mood episode was almost always depressive.

Conclusions:  Despite a specific genetic risk, BD began with non‐specific psychopathology and/or depressive disorders in a majority of offspring. Therefore, diagnosis based only on cross‐sectional assessment of symptoms appears to be insufficient for the accurate early detection of emerging BD. Other parameters such as family history and associated antecedents should be taken into account.
Antidepressant‐associated switches from depression to mania in severe bipolar disorder
Authors: Carlson Gabrielle A , Finch Stephen J , Fochtmann Laura J , Ye Qing , Wang Qing , Naz Bushra , Bromet Evelyn J
Published: September 2010

Objectives:  To determine whether switching from depression to mania is part of the natural history of bipolar illness or results from antidepressant (AD) treatment by examining bipolar patients with psychosis early in their illness course.

Methods:  A multi‐facility cohort of 123 first‐admission inpatients, aged 15–60 years, with DSM‐IV bipolar disorder (BD) with psychotic features, was followed for four years, and 76 individuals experienced at least one episode of depression. Frequency of and risk factors for switches from depression to mania, time to switch, and duration of the subsequent manic episode were examined in relation to AD use (with anti‐manic and/or antipsychotic medications).

Results:  The 76 respondents experienced 113 depressive episodes. Those prescribed ADs had more depressive episodes and spent more time depressed than non‐users. A total of 23 depressive episodes in 17 respondents ended in a manic/hypomanic/mixed episode (20%). The time to switch and duration of the subsequent manic episode were not significantly different for the seven respondents and nine episodes involving AD treatment versus the 10 respondents and 14 episodes without ADs. None of the risk factors (age of onset ≤18 years, childhood psychopathology, depressive first episode, substance abuse at index admission, bipolar family history, type of AD used) was associated with switching.

Conclusions:  In this sample with severe BD, switching from depression to mania was not associated with AD treatment. Respondents who experienced switching appeared to have a more relentless form of BD. In only a few did ADs appear to be responsible for the switch.
Factors associated with mental health service utilization among bipolar youth
Authors: Rizzo Christie J , Esposito‐Smythers Christianne , Swenson Lance , Birmaher Boris , Ryan Neal , Strober Michael , Chiappetta Laurel , Valeri Sylvia , Hunt Jeffrey , Axelson David , Leonard Henrietta , Keller Martin
Published: September 2010

Objectives:  This study aims to characterize patterns of mental health service utilization within a sample of bipolar youth. Demographic variables, youth bipolar characteristics, youth comorbid conditions, and parental psychopathology were examined as predictors of treatment utilization across different levels of care.

Methods:  A total of 293 bipolar youth (aged 7–17 years) and their parents completed a diagnostic interview, family psychiatric history measures, and an assessment of mental health service utilization. Demographic and clinical variables were measured at baseline and mental health service use was measured at the six‐month follow‐up.

Results:  Approximately 80% of bipolar youth attended psychosocial treatment services over the span of 6 months. Of those who attended treatment, 67% attended only outpatient services, 22% received inpatient/partial hospitalization, and 12% received residential/therapeutic school‐based services. Using multinomial logistic regression, older age, female gender, and bipolar characteristics, including greater symptom severity and rapid cycling, were found to predict higher levels of care. Youth suicidal and non‐suicidal self‐injurious behavior, comorbid conduct disorder, and parental substance use disorders also predicted use of more restrictive treatment settings.

Conclusions:  Results underscore the importance of assessing for and addressing suicidality, comorbid conduct disorder, and parental substance use disorders early in the treatment of bipolar youth to potentially reduce the need for more restrictive levels of care.
Complicated grief and impaired sleep in patients with bipolar disorder
Authors: Maytal Guy , Zalta Alyson K , Thompson Elizabeth , Chow Candice W , Perlman Carol , Ostacher Michael J , Pollack Mark H , Shear Katherine , Simon Naomi M
Published: September 2010

Objectives:  To examine the relationship of sleep disturbance with complicated grief (CG) in patients with bipolar disorder (BD).

Methods:  Adults with DSM‐IV BD were asked if they ever experienced significant loss and, if so, completed the Inventory of Complicated Grief. Subjective sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). The association of CG with sleep disturbance was assessed in univariate t‐tests, and in multivariate analyses controlling for the presence of anxiety disorder comorbidity and current bipolar recovery status.

Results:  Individuals with CG had significantly higher mean PSQI scores (10.9 versus 7.9, p = 0.003) than those without CG. Further, within the group of BD participants who had experienced a significant loss, those with CG had significantly poorer sleep (p = 0.01). CG remained significantly associated with greater sleep impairment after adjustment for comorbid anxiety disorder and bipolar mood state. This additive impairment in sleep with CG comorbidity was evident for four of the PSQI component scales: sleep quality, sleep duration, sleep efficiency and sleep disturbance.

Conclusions:  Our data indicate a significant association of CG with poor sleep in individuals with BD. Disturbed sleep may be a mechanism by which CG increases the burden of illness in BD.
A prospective open‐label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder
Authors: Biederman Joseph , Mick Eric , Spencer Thomas , Dougherty Meghan , Aleardi Megan , Wozniak Janet
Published: September 2010

Objective:  To assess the effectiveness and tolerability of ziprasidone for treating pediatric mania.

Methods:  This was an eight‐week, open‐label, prospective study of ziprasidone monotherapy (57.3 ± 33.9 mg/day) in 21 bipolar youth [manic, mixed, or bipolar not otherwise specified (NOS); 6–17 years old]. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions‐Improvement scale (CGI‐I), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self‐reports, vital signs, weight monitoring, and laboratory analysis.

Results:  Fourteen of the 21 youth (67%) completed the study. Ziprasidone treatment was associated with clinically and statistically significant improvement in mean YMRS scores (−10.8 ± 8.4, p < 0.0001) and 57% had a CGI‐I ≤2 at endpoint. Ziprasidone was well tolerated with no statistically significant increase in body weight (0.6 ± 0.4 kg, p = 0.2) or QTc interval (−3.7 ± 4.7, p = 0.5).

Conclusions:  Open‐label ziprasidone treatment was associated with a significant short‐term improvement of symptoms of pediatric bipolar disorder. Future placebo‐controlled, double‐blind studies are warranted.
Light therapy for bipolar disorder: a case series in women
Authors: Sit Dorothy , Wisner Katherine L , Hanusa Barbara H , Stull Stacy , Terman Michael
Published: September 2010

Objectives:  To perform a dose‐ranging safety and efficacy study of bright light therapy for depression in women with bipolar disorder (BD).

Methods:  Nine women with DSM‐IV BD I or II in the depressed phase were exposed to 50 lux (illuminance at the receiving surface) red light for two weeks, after which they received 7,000 lux light therapy for two‐week epochs of 15, 30 and 45 min daily. The Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement and the Mania Rating Scale were used to assess mood symptoms. Four patients received morning light and five patients received midday light.

Results:  Three of the four subjects treated with morning light developed mixed states. The fourth subject achieved a full, sustained response. To decrease the risk of inducing mixed episodes, we changed the time of light exposure to midday. Of the five women who received midday light therapy, two achieved full response and two showed early improvement but required a dose increase to sustain response. One woman remained depressed with 45 min of midday light but responded fully to a switch to morning light, 30 min daily.

Conclusions:  Women with bipolar illness are highly sensitive to morning bright light treatment; the induction of mixed states is a substantial risk. Initiating treatment with a brief duration (15 min) of midday light for bipolar depression is advisable.
Psychotic features in bipolar and unipolar depression
Authors: Goes Fernando S , Sadler Bradley , Toolan Jennifer , Zamoiski Rachel D , Mondimore Francis M , MacKinnon Dean F , Schweizer Barbara ,   The Bipolar Disorder Phenome Group, Raymond DePaulo J , Potash James B
Published: September 2010

Background:  While some prior studies have found higher rates of psychotic depression in those with bipolar disorder or a bipolar relative, others have failed to confirm these observations. We examined the relationship of psychotic depression to polarity in several large familial samples of mood disorder.

Methods:  A total of 4,724 subjects with major mood disorder in three family studies on the genetics of bipolar I disorder (BPI) or recurrent major depressive disorder (MDDR) were administered semi‐structured interviews by clinicians. Determination of psychotic features was based on a report of hallucinations and/or delusions during the most severe depressive episode in the Schedule for Affective Disorders and Schizophrenia‐Lifetime Version or the Diagnostic Interview for Genetic Studies interview. Rates of psychotic depression were calculated by diagnostic category and comparisons were made between diagnoses within and across studies using the generalized estimating equation.

Results:  A diagnosis of BPI disorder was strongly predictive of psychotic features during depression compared to MDDR [odds ratio (OR) = 4.61, p < 0.0005]. Having bipolar II compared to MDDR was not predictive of psychosis (OR = 1.05, p = 0.260), nor was having a family history of BPI in MDDR subjects (OR = 1.20, p = 0.840).

Conclusions:  Psychotic features during a depressive episode increased the likelihood of a BPI diagnosis. Prospective studies are needed to confirm these findings. The potential genetic underpinnings of psychotic depression warrant further study.
Phenomenology of mixed states: a principal component analysis study
Authors: Bertschy G , Gervasoni N , Favre S , Liberek C , Ragama‐Pardos E , Aubry J‐M , Gex‐Fabry M , Dayer A
Published: September 2010

Objectives:  To contribute to the definition of external and internal limits of mixed states and study the place of dysphoric symptoms in the psychopathology of mixed states.

Methods:  One hundred and sixty‐five inpatients with major mood episodes were diagnosed as presenting with either pure depression, mixed depression (depression plus at least three manic symptoms), full mixed state (full depression and full mania), mixed mania (mania plus at least three depressive symptoms) or pure mania, using an adapted version of the Mini International Neuropsychiatric Interview (DSM‐IV version). They were evaluated using a 33‐item inventory of depressive, manic and mixed affective signs and symptoms.

Results:  Principal component analysis without rotation yielded three components that together explained 43.6% of the variance. The first component (24.3% of the variance) contrasted typical depressive symptoms with typical euphoric, manic symptoms. The second component, labeled ‘dysphoria’, (13.8%) had strong positive loadings for irritability, distressing sensitivity to light and noise, impulsivity and inner tension. The third component (5.5%) included symptoms of insomnia. Median scores for the first component significantly decreased from the pure depression group to the pure mania group. For the dysphoria component, scores were highest among patients with full mixed states and decreased towards both patients with pure depression and those with pure mania.

Conclusions:  Principal component analysis revealed that dysphoria represents an important dimension of mixed states.
A near‐infrared spectroscopy study of prefrontal cortex activation during a verbal fluency task and carbon dioxide inhalation in individuals with bipolar disorder
Authors: Matsuo Koji , Kouno Toshiaki , Hatch John P , Seino Kai , Ohtani Toshiyuki , Kato Nobumasa , Kato Tadafumi
Published: September 2010

Objectives:  There is evidence of prefrontal cortex (PFC) dysfunction in patients with bipolar disorder (BP). Magnetic resonance and neuropathological studies show abnormalities of the brain microvasculature in patients with BP. However, the underlying biological mechanisms are not well understood. We investigated the relationship between activation of the PFC during a cognitive task and the vascular function in response to a physiological task in patients with BP.

Methods:  Fourteen euthymic patients with BP and 14 control subjects matched for age, sex, and education were recruited. We examined the response of the PFC during a verbal fluency task and during 5% CO2 inhalation using a 24‐channel near‐infrared spectroscopy imaging system to measure alteration of oxygenated and deoxygenated hemoglobin.

Results:  The BP patients showed a significantly lower level of PFC activation during the cognitive task compared to the healthy controls, but the task‐performance of the BP patients was not significantly different from that of the controls. The vascular response of the BP patients to CO2 was not significantly different from that of controls.

Conclusions:  This study suggests functional hypoactivation of the PFC during a cognitive load in patients with BP while they are in a euthymic state. The mechanism of this hypoactivation is different from that of vascular regulation in response to a physiological stimulus.
White matter abnormalities in children with and at risk for bipolar disorder
Authors: Frazier Jean A , Breeze Janis L , Papadimitriou George , Kennedy David N , Hodge Steven M , Moore Constance M , Howard James D , Rohan Michael P , Caviness Verne S , Makris Nikos
Published: September 2010

Objectives:  Diffusion tensor magnetic resonance imaging (DT‐MRI) assesses the integrity of white matter (WM) tracts in the brain. Children with bipolar disorder (BPD) may have WM abnormalities that precede illness onset. To more fully examine this possibility, we scanned children with DSM‐IV BPD and compared them to healthy peers and children at risk for BPD (AR‐BPD), defined as having a first‐degree relative with the disorder.

Methods:  Ten children with BPD, eight healthy controls (HC), and seven AR‐BPD, similar in age, had MRI scans on a 1.5 Tesla GE scanner, including a standard DT‐MRI sequence (T2‐EPI) with 25 axial slices. Fractional anisotropy (FA) values were compared between groups to determine regions of significant difference (p < 0.05).

Results:  Compared to HC, children with BPD had decreased FA in right and left superior frontal tracts, including the superior longitudinal fasciculus I (SLF I) and the cingulate‐paracingulate WM (CG‐PACWM). In addition, the BPD group had reduced FA in left orbital frontal WM and the right corpus callosum body. Compared to AR‐BPD, children with BPD showed reduced FA in the right and left CG‐PACWM. Both the BPD and AR‐BPD groups showed reduced FA relative to HC in bilateral SLF I.

Conclusions:  The bilateral SLF I finding in both the BPD and AR‐BPD groups may represent a trait‐based marker or endophenotype of the disorder. The finding of decreased FA in the right and left CG‐PACWM in children with BPD compared to the other two groups may represent a disease‐state related finding.
Familial aggregation of postpartum mood symptoms in bipolar disorder pedigrees
Authors: Payne Jennifer L , MacKinnon Dean F , Mondimore Francis M , McInnis Melvin G , Schweizer Barbara , Zamoiski Rachel B , McMahon Francis J , Nurnberger John I , Rice John P , Scheftner William , Coryell William , Berrettini Wade H , Kelsoe John R , Byerley William , Gershon Elliot S , Raymond DePaulo J , Potash James B
Published: September 2010

Objectives:  We sought to determine if postpartum mood symptoms and depressive episodes exhibit familial aggregation in bipolar I pedigrees.

Methods:  A total of 1,130 women were interviewed with the Diagnostic Interview for Genetic Studies as part of the National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative Study and were asked whether they had ever experienced mood symptoms within four weeks postpartum. Women were also asked whether either of two major depressive episodes described in detail occurred postpartum. We examined the odds of postpartum mood symptoms in female siblings, who had previously been pregnant and had a diagnosis of bipolar I, bipolar II, or schizoaffective (bipolar type) disorders (n = 303), given one or more relatives with postpartum mood symptoms.

Results:  The odds ratio for familial aggregation of postpartum mood symptoms was 2.31 (p = 0.011) in an Any Mood Symptoms analysis (n = 304) and increased to 2.71 (p = 0.005) when manic symptoms were excluded, though this was not significantly different from the Any Mood Symptoms analysis. We also examined familial aggregation of postpartum major depressive episodes; however, the number of subjects was small.

Conclusions:  Limitations of the study include the retrospective interview, the fact that the data were collected for other purposes and the inability to control for such factors as medication use. Taken together with previous studies, these data provide support for the hypothesis that there may be a genetic basis for the trait of postpartum mood symptoms generally and postpartum depressive symptoms in particular in women with bipolar disorder. Genetic linkage and association studies incorporating this trait are warranted.
Pituitary gland volume in adolescent and young adult bipolar and unipolar depression
Authors: MacMaster Frank P , Leslie Ronald , Rosenberg David R , Kusumakar Vivek
Published: September 2010

Objectives:  Few studies have examined pituitary gland size in mood disorders, particularly in adolescents. We hypothesized increase in the pituitary gland size in early‐onset mood disorders.

Methods:  Thirty subjects between the ages of 13 and 20 years participated in the study. Three groups (control, bipolar I depression and unipolar depression) of 10 subjects each (4 male, 6 female) underwent volumetric magnetic resonance imaging at 1.5 T.

Results:  Analysis of covariance (covarying for age, sex and intracranial volume) revealed a significant difference in pituitary gland volume amongst the groups [F(2,24) = 7.092, p = 0.014]. Post hoc analysis revealed that controls had a significantly smaller pituitary gland volume than both bipolar patients (p = 0.019) and depressed patients (p = 0.049). Bipolar and depressed subjects did not differ significantly from each other with regard to pituitary gland volume (p = 0.653). Control females had larger pituitary glands than control males [F(1,8) = 10.523, p = 0.012], but no sex differences were noted in the mood disorder groups.

Conclusions:  Pituitary glands are enlarged in adolescents with mood disorders compared to controls. Healthy young females have larger pituitary glands than males, but such a difference is not evident in individuals with unipolar depression or bipolar disorder. These findings provide new evidence of abnormalities of the pituitary in early onset mood disorders, and are consistent with neuroendocrine dysfunction in early stages of such illnesses.
Psychotic phenomena in 257 young children and adolescents with bipolar I disorder: delusions and hallucinations (benign and pathological)
Authors: Tillman Rebecca , Geller Barbara , Klages Tricia , Corrigan Meg , Bolhofner Kristine , Zimerman Betsy
Published: September 2010

Objectives:  In contrast to studies of adult bipolar I disorder (BP‐I), there is a paucity of data on psychotic phenomena in child BP‐I. Therefore, the aim of this work was to describe delusions and hallucinations in pediatric BP‐I.

Methods:  Subjects were 257 participants, aged 6–16, in either of two large, ongoing, NIMH‐funded studies, ‘Phenomenology and Course of Pediatric Bipolar Disorders’ or ‘Treatment of Early Age Mania (TEAM)’. All subjects had current DSM‐IV BP‐I (manic or mixed phase) with a Children’s Global Assessment Scale score ≤60 (definite clinical impairment), and all had cardinal mania symptoms (i.e., elation and/or grandiosity). Comprehensive assessments included the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH‐U‐KSADS), which was administered to parents about their children and separately to children about themselves by experienced research clinicians. The WASH‐U‐KSADS contains modules for developmentally child‐age‐specific manifestations of numerous categories of psychotic phenomena.

Results:  Psychosis was present in 76.3% (n = 196) of subjects, which included 38.9% (n = 100) with delusions, 5.1% (n = 13) with pathological hallucinations, and 32.3% (n = 83) with both. The most common delusion was grandiose (67.7%, n = 174), and the most common pathological hallucination was visual (16.0%, n = 41). Benign hallucinations occurred in 43.6% (n = 112). A median split by age yielded 6–9 year‐olds (n = 139) and 10–16 year‐olds (n = 118). Analyses of these two groups, and of 6, 7, 8, and 9 year‐olds separately, found no significant differences in psychotic phenomena.

Conclusions:  Counterintuitively, psychosis was equally prevalent in 6–9 compared to 10–16 year‐olds. High prevalence of psychosis in child BP‐I warrants focus in intervention strategies and is consistent with increasing evidence of the severity of child‐versus adult‐onset BP‐I.
Homicidal ideation with intent during a manic episode triggered by antidepressant medication in a man with brain injury
Authors: Dealberto Marie‐José , Marino Josie , Bourgon Luc
Published: September 2010

Background:  Mood disorders are more frequent after brain injury and both depressive and manic episodes are associated in these patients with an increased risk of aggression. Antidepressant medications are associated with a risk of manic induction.

Case report:  We describe a case of homicidal ideation with intent during the onset of a manic episode in a patient with prior brain injury on antidepressant medication at low dosage. The manic episode could have been secondary to brain injury and/or triggered by antidepressant medications. This case raises the possibility of the sensitizing role of brain injury for antidepressant‐induced mania.

Conclusions:  Further studies are needed to assess the role of brain injury as a risk factor for antidepressant‐induced mania. Physicians should be cautious when prescribing antidepressants to patients with prior brain injury and inform them and their relatives of the possibility of a switch into mania.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: REGULATION OF RENAL TUBULAR SODIUM TRANSPORT BY ANGIOTENSIN II AND ATRIAL NATRIURETIC FACTOR
Authors: Harris Peter J , Hiranyachattada Siriphun , Antoine Arianne M , Walker Lesley , Reilly Angela M , Eitle Eveline
Published: September 2010

The effects of angiotensin II (AngII) on water and electrolyte transport are biphasic and dose‐dependent, such that low concentrations (10−12to 10−9mol/L) stimulate reabsorption and high concentrations (10−7to 10−6mol/L) inhibit reabsorption. Similar dose‐response relationships have been obtained for luminal and peritubular addition of AngII.

The cellular responses to AngII are mediated via AT1receptors coupled via G‐regulatory proteins to several possible signal transduction pathways. These include the inhibition of adenylyl cyclase, activation of phospholipases A2, C or D and Ca2+release in response to inositol‐1,4,5,‐triphosphate or following Ca2+channel opening induced by the arachidonic acid metabolite 5,6,‐epoxy‐eicosatrienoic acid. In the brush border membrane, transduction of the AngII signal involves phospholipase A2, but does not require second messengers.

Angiotensin II affects transepithelial sodium transport by modulation of Na+/H+exchange at the luminal membrane and Na+/HCO3cotransport, Na+/K+‐ATPase activity and K+conductance at the basolateral membrane.

Atrial natriuretic factor (ANF) does not appear to affect proximal tubular sodium transport directly, but acts via specific receptors on the basolateral and brush border membranes to raise intracellular cGMP levels and inhibit AngII‐stimulated transport.

It is concluded that there is a receptor‐mediated action of ANF on proximal tubule reabsorption acting via elevation of cGMP to inhibit AngII‐stimulated sodium transport. This effect is exerted by peptides delivered at both luminal and peritubular sides of the epithelium and provides a basis for the modulation by ANF of proximal glomerulotubular balance. The evidence reviewed supports the concept that in the proximal tubule, AngII and ANF act antagonistically in their roles as regulators of extracellular fluid volume.
Proceedings of the Symposium ‘Angiotensin AT1Receptors: From Molecular Physiology to Therapeutics’: EXPERIENCE WITH ANGIOTENSIN II ANTAGONISTS IN HYPERTENSIVE PATIENTS
Authors: Waeber Bernard , Burnier Michel , Nussberger Jürg , Brunner Hans R
Published: September 2010

The availability of orally active specific angiotensin receptor antagonists (AT1antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin‐angiotensin system in the pathogenesis of cardiovascular disease.

The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin‐converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin‐angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs.

The most common side effect of ACE inhibitors, dry cough, does not occur with AT1antagonists, which confirms the long‐held view that this untoward effect of the ACE inhibitors is due to renin‐angiotensin‐independent mechanisms.

Long‐term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.
EFFECTS OF TAIL FAT ON HALOTHANE BIOTRANSFORMATION IN FAT‐TAILED SHEEP
Authors: Sharifi S , Vesal N
Published: September 2010

1. The aim of the present study was to evaluate the effects of tail fat on halothane biotransformation following similar anaesthetic exposure in intact sheep and sheep with a ligated median sacral artery.

2. A prospective randomized experimental study was performed using 12 healthy, 10–12‐month‐old female sheep.

3. Sheep were randomly divided into two groups of six animals each and were anaesthetized twice at 2 weekly intervals. After mask induction with halothane in 100% oxygen, sheep were intubated and anaesthesia was maintained for 3 h using a rebreathing system. Serum fluoride concentration (SFC) was measured at 0, 1, 3, 6, 12, 24, 48 and 72 h following the induction of anaesthesia. Serum biochemistry was also evaluated at baseline and 72 h after anaesthesia. Induction and extubation times and time to sternal recumbency were also recorded during anaesthetic induction and recovery. Prior to the second anaesthesia (2 weeks later), the median sacral artery (MSA) was ligated under epidural anaesthesia in the experimental group. Sheep in the control group underwent sham operation. All sheep were anaesthetized as before.

4. Following the first halothane anaesthesia, SFC was significantly increased from 3 to 48 h compared with baseline. In the second stage of the experiment, the increases in SFC in the control group were similar to those seen in the first stage of the experiment. However, in MSA‐ligated sheep, the increases in SFC were only significant between 3 and 12 h compared with baseline. The SFC was significantly higher in intact sheep from 3 to 72 h compared with the MSA‐ligated group. Extubation and sternal recumbency times were significantly longer in intact sheep.

5. Ligation of the MSA in fat‐tailed sheep induced a significant reduction in SFC, suggesting that the presence of tail fat substantially affects halothane metabolism during the peri‐anaesthetic period in sheep. The greater extent of halothane biotransformation may be clinically important in, otherwise normal, obese patients.
EFFECTS OF MELATONIN ON LIPID PEROXIDATION and ANTI‐OXIDANT ENZYME ACTIVITY IN RATS WITH EXPERIMENTALLY INDUCED HYPERTHYROIDISM
Authors: Baydas Burhanettin , Meral Ismail
Published: September 2010

1. The present study was designed to investigate the effects of high‐dose melatonin on lipid peroxidation and anti‐oxidant enzyme activity in rats with experimentally induced hyperthyroidism.

2. Twenty‐four albino male rats, weighing 240–260 g, were randomly allotted into one of three experimental groups (control, hyperthyroid and hyperthyroid + melatonin treatment), with each group containing eight animals. Hyperthyroidism was induced by a daily with i.p. injection of 200 µg l‐thyroxine for 30 days. In addition to l‐thyroxin treatment, rats in the hyperthyroid + melatonin treatment group were also given daily i.p. injections of 10 mg/kg melatonin on the last 10 days of l‐thyroxine treatment. Control animals received injections of an equivalent volume of saline solution. Rats received the last injection 24 h before being killed.

3. At the end of the experiment, rats in all three groups were fasted for 12 h and killed by cardiac puncture under ether anaesthesia. Blood samples were taken for the determination of malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels and concentrations of tri‐iodothyronine (T3) and thyroxine (T4).

4. It was found that MDA and SOD levels and concentrations of T3 and T4 were higher and the GSH level was lower in rats with hyperthyroidism compared with controls. Melatonin treatment decreased the elevated MDA and SOD levels and increased the lowered GSH level to control levels in rats with hyperthyroidism, but did not ameliorate the concentrations of T3 and T4.

5. It was concluded that high‐dose melatonin treatment may decrease the hyperthyroidism‐induced disturbances of lipid peroxidation and anti‐oxidant enzyme activity and oxidative damage.
EFFECT OF NAPROXEN, A NON‐SELECTIVE CYCLO‐OXYGENASE INHIBITOR, ON PENTYLENETETRAZOL‐INDUCED KINDLING IN MICE
Authors: Dhir Ashish , Naidu Pattipati S , Kulkarni Shrinivas K
Published: September 2010

1. Epilepsy is one of the major neurological disorders of the brain, affecting approximately 0.5–1.0% of the population worldwide. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy.

2. Cyclo‐oxygenase (COX) is the rate‐limiting enzyme in the production of prostaglandins and, as such, is a key target for many anti‐inflammatory drugs. Cyclo‐oxygenase has been reported to play a significant role in neurodegeneration. Recent studies have reported that COX plays a significant role in the pathophysiology of epilepsy.

3. The aim of the present study was to explore the possible role of COX and the effect of COX inhibitors in epilepsy.

4. Kindling is a chronic model of epilepsy. In the present study, kindling was induced in mice by chronic administration of a subconvulsive dose of pentylenetetrazole (PTZ; 40 mg/kg) on every other day for a period of 15 days. Naproxen was administered daily 45 min before PTZ or vehicle. The kindling score was recorded after PTZ administration. Seizure severity was measured according to a prevalidated scoring scale. Biochemical estimations were performed immediately after recording behavioural parameters on the 16th day of PTZ treatment.

5. Chronic treatment with PTZ significantly induced kindling in mice. Pretreatment with the non‐selective COX inhibitor naproxen (7 and 14 mg/kg, i.p.) showed significant protection against PTZ‐induced kindling in mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation and nitrite levels (NO levels), but decreased reduced glutathione (GSH) levels in brain homogenates.

6. In conclusion, the results of the present study strongly suggest that COX plays an important role in the pathophysiology of PTZ‐induced kindling in mice and that COX inhibitors could be a useful neuroprotective strategy for the treatment of epilepsy.