Prefrontal cortical and striatal activity to happy and fear faces in bipolar disorder is associated with comorbid substance abuse and eating disorder

Background: The spectrum approach was used to examine contributions of comorbid symptom dimensions of substance abuse and eating disorder to abnormal prefrontal-cortical and subcortical-striatal activity to happy and fear faces previously demonstrated in bipolar disorder (BD). Method: Fourteen remitted BD-type I and sixteen healthy individuals viewed neutral, mild and intense happy and fear faces in two event-related fMRI experiments. All individuals completed Substance-Use and Eating-Disorder Spectrum measures. Region-of-Interest analyses for bilateral prefrontal and subcortical-striatal regions were performed. Results: BD individuals scored significantly higher on these spectrum measures than healthy individuals (p<0.05), and were distinguished by activity in prefrontal and subcortical-striatal regions. BD relative to healthy individuals showed reduced dorsal prefrontal-cortical activity to all faces. Only BD individuals showed greater subcortical-striatal activity to happy and neutral faces. In BD individuals, negative correlations were shown between substance use severity and right PFC activity to intense happy faces (p<0.04), and between substance use severity and right caudate nucleus activity to neutral faces (p<0.03). Positive correlations were shown between eating disorder and right ventral putamen activity to intense happy (p<0.02) and neutral faces (p<0.03). Exploratory analyses revealed few significant relationships between illness variables and medication upon neural activity in BID individuals. Limitations: Small sample size of predominantly medicated BD individuals. Conclusion: This study is the first to report relationships between comorbid symptom dimensions of substance abuse and eating disorder and prefrontal-cortical and subcortical-striatal activity to facial expressions in BD. Our findings suggest that these comorbid features may contribute to observed patterns of functional abnormalities in neural systems underlying mood regulation in BD. (C) 2009 Elsevier B.V. All rights reserved.

Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra-and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.

Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Pulmonary involvement in pleural tuberculosis: How often does it mean disease activity?

Objective: To evaluate in chest X-rays and high-resolution computed tomographies of patients with pleural tuberculosis, the incidence of parenchymal and mediastinal lung lesions suggestive of active disease. Methods: Prospective study (2008-2009) evaluating the radiographic and tomographic abnormalities of 88 HIV-negative patients with pleural tuberculosis (unilateral effusion). The images were reviewed by 3 independent specialists, and the observed changes were classified according to previously established criteria: presence or absence of signs suggestive of disease activity, and nonspecific findings. Results: Abnormal changes were observed in chest X-rays of 22 (25%) patients and in the computed tomography of 55 (63%). Images compatible with active pulmonary tuberculosis were detected by radiography in 9 (10%) patients and by tomography in 38 (43%). Only 4 (4.5%) patients had tomography images suggestive of residual disease. Conclusion: The present study demonstrates that pulmonary involvement is quite common in pleural tuberculosis. This finding is mainly observed in high-resolution computed tomography and has important epidemiological implications, since patients with pleural tuberculosis are significant sources of infection and disease dissemination. (C) 2011 Elsevier Ltd. All rights reserved.

Orbitofrontal cortex gray matter volumes in bipolar disorder patients: a region-of-interest MRI study

Objectives: Functional and postmortem studies suggest that the orbitofrontal cortex (OFC) is involved in the pathophysiology of bipolar disorder (BD). This anatomical magnetic resonance imaging (MRI) study examined whether BD patients have smaller OFC gray matter volumes compared to healthy comparison subjects (HC). Methods: Twenty-eight BD patients were compared to 28 age- and gender-matched HC. Subjects underwent a 1.5T MRI with 3D spoiled gradient recalled acquisition. Total OFC and medial and lateral subdivisions were manually traced by a blinded examiner. Images were segmented and gray matter volumes were calculated using an automated method. Results: Analysis of covariance, with intracranial volume as covariate, showed that BD patients and HC did not differ in gray matter volumes of total OFC or its subdivisions. However, total OFC gray matter volume was significantly smaller in depressed patients (n = 10) compared to euthymic patients (n = 18). Moreover, total OFC gray matter volumes were inversely correlated with depressive symptom intensity, as assessed by the Hamilton Depression Rating Scale. OFC gray matter volumes were not related to lithium treatment, age at disease onset, number of episodes, or family history of mood disorders. Conclusions: Our results suggest that abnormal OFC gray matter volumes are not a pervasive characteristic of BD, but may be associated with specific clinical features of the disorder.

Fear of heights: cognitive performance and postural control

Fear of heights, or acrophobia, is one of the most frequent subtypes of specific phobia frequently associated to depression and other anxiety disorders. Previous evidence suggests a correlation between acrophobia and abnormalities in balance control, particularly involving the use of visual information to keep postural stability. This study investigates the hypotheses that (1) abnormalities in balance control are more frequent in individuals with acrophobia even when not exposed to heights, that (2) acrophobic symptoms are associated to abnormalities in visual perception of movement; and that (3) individuals with acrophobia are more sensitive to balance-cognition interactions. Thirty-one individuals with specific phobia of heights and thirty one non-phobic controls were compared using dynamic posturography and a manual tracking task. Acrophobics had poorer performance in both tasks, especially when carried out simultaneously. Previously described interference between posture control and cognitive activity seems to play a major role in these individuals. The presence of physiologic abnormalities is compatible with the hypothesis of a non-associative acquisition of fear of heights, i.e., not associated to previous traumatic events or other learning experiences. Clinically, this preliminary study corroborates the hypothesis that vestibular physical therapy can be particularly useful in treating individuals with fear of heights.

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: Significant effects of gender and trait anxiety

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high-versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication load

To examine abnormal patterns of frontal cortical-subcortical activity in response to emotional stimuli in euthymic individuals with bipolar disorder type I in order to identify trait-like, pathophysiologic mechanisms of the disorder. We examined potential confounding effects of total psychotropic medication load and illness variables upon neural abnormalities. We analyzed neural activity in 19 euthymic bipolar and 24 healthy individuals to mild and intense happy, fearful and neutral faces. Relative to healthy individuals, bipolar subjects had significantly increased left striatal activity in response to mild happy faces (p < 0.05, corrected), decreased right dorsolateral prefrontal cortical (DLPFC) activity in response to neutral, mild and intense happy faces, and decreased left DLPFC activity in response to neutral, mild and intense fearful faces (p < 0.05, corrected). Bipolar and healthy individuals did not differ in amygdala activity in response to either emotion. In bipolar individuals, there was no significant association between medication load and abnormal activity in these regions, but a negative relationship between age of illness onset and amygdala activity in response to mild fearful faces (p = 0.007). Relative to those without comorbidities, bipolar individuals with comorbidities showed a trend increase in left striatal activity in response to mild happy faces. Abnormally increased striatal activity in response to potentially rewarding stimuli and decreased DLPFC activity in response to other emotionally salient stimuli may underlie mood instabilities in euthymic bipolar individuals, and are more apparent in those with comorbid diagnoses. No relationship between medication load and abnormal neural activity in bipolar individuals suggests that our findings may reflect pathophysiologic mechanisms of the illness rather than medication confounds. Future studies should examine whether this pattern of abnormal neural activity could distinguish bipolar from unipolar depression.

Illness duration and total brain gray matter in bipolar disorder: Evidence for neurodegeneration?

Previous studies have suggested that bipolar disorder (BD) is associated with alterations in neuronal plasticity, but the effects of the progression of illness on brain anatomy have been poorly investigated. We studied the correlation between length of illness, age, age at onset, and the number of previous episodes and total brain, total gray, and total white matter volumes in BD, unipolar (UP) and healthy control (HC) subjects. Thirty-six BD, 31 UP and 55 HCs underwent a 1.5 T brain magnetic resonance imaging scan, and gray and white matter volumes were manually traced blinded to the subjects` diagnosis. Partial correlation analysis showed that length of illness was inversely correlated with total gray matter volume after adjusting for total intracranial volume in BD (r(p)=-0.51; p=0.003) but not in UP subjects (r(p)=-0.23; p=0.21). Age at illness onset and the number of previous episodes were not significantly correlated with gray matter volumes in BD or UP subjects. No significant correlation with total white matter volume was observed. These results suggest that the progression of illness may be associated with abnormal cellular plasticity. Prospective longitudinal studies are necessary to elucidate the long-term effects of illness progression on brain structure in major mood disorders. (C) 2008 Published by Elsevier B.V.

Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics

Context Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulatioin in BD. Objective: To use tract-based spatial statistics (TBSS) to examine VVM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects. Design: Cross-sectional, case-control, whole-brain DTI using TBSS. Setting: University research institute. Participants: Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type 1 (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]). Main Outcome Measures: Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables. Results: Subjects with BD vs controls had significantly greater FA (t > 3.0, P <=.05 corrected) in the left uncinate fasciculus (reduced radial diffusivity distally and increased longitudinal diffusivity centrally), left optic radiation (increased longitudinal diffusivity), and right anterothalamic radiation (no significant diffusivity change). Subjects with BD vs controls had significantly reduced FA (t > 3.0, P <=.05 corrected) in the right uncinate fasciculus (greater radial diffusivity). Among subjects with BD, significant negative correlations (P <.01) were found between age and FA in bilateral uncinate fasciculi and in the right anterothalamic radiation, as well as between medication load and FA in the left optic radiation. Decreased FA (P <.01) was observed in the left optic radiation and in the right anterothalamic radiation among subjects with BD taking vs those not taking mood stabilizers, as well as in the left optic radiation among depressed vs remitted subjects with BD. Subjects having BD with vs without lifetime alcohol or other drug abuse had significantly decreased FA in the left uncinate fasciculus. Conclusions: To our knowledge, this is the first study to use TBSS to examine WM in subjects with BD. Subjects with BD vs controls showed greater WM FA in the left OMPFC that diminished with age and with alcohol or other drug abuse, as well as reduced WM FA in the right OMPFC. Mood stabilizers and depressed episode reduced WM FA in left-sided sensory visual processing regions among subjects with BD. Abnormal right vs left asymmetry in FA in OMPFC WM among subjects with BD, likely reflecting increased proportions of left-sided longitudinally aligned and right-sided obliquely aligned myelinated fibers, may represent a biologic mechanism for mood dysregulation in BD.

Urogenital tuberculosis in a patient with AIDS: an unusual presentation

Background A 38-year-old man with AIDS presented to hospital with a 3-month history of fevers, bilateral lumbar pain, dysuria and increased urinary frequency. Six years earlier he had received 6 months` treatment for pulmonary tuberculosis. At presentation, he was on antiretroviral therapy with a combination of efavirenz, stavudine and lamivudine. Investigations Physical examination, evaluation of HIV viral load, CD4 count, measurement of serum hemoglobin concentration, white blood cell count, urinalysis, urine culture for usual pathogens, direct smear and urine culture for Mycobacterium tuberculosis, chest radiography, abdominal CT, measurement of serum creatinine concentration and estimated creatinine clearance. Diagnosis Urogenital tuberculosis. Management The patient`s symptoms and radiological abnormalities persisted despite antibiotic therapy for presumed bacterial infection. After urine culture had confirmed M. tuberculosis infection, he was administered pharmacological treatment comprising isoniazid, rifampin, pyrazinamide and ethambutol for 2 months, with isoniazid and rifampin given for a further 7 months. His symptoms improved within a few days of initiating treatment. Six months after treatment started, CT revealed a nonfunctioning right kidney and a functional left kidney with areas of scarring. The patient refused right nephrectomy, and completed his pharmacological treatment. No evidence of disease recurrence was observed during 2 years of follow-up.

High frequency of submicroscopic chromosomal imbalances in patients with syndromic craniosynostosis detected by a combined approach of microsatellite segregation analysis, multiplex ligation-dependent probe amplification and array-based comparative genome hybridisation

We present the first comprehensive study, to our knowledge, on genomic chromosomal analysis in syndromic craniosynostosis. In total, 45 patients with craniosynostotic disorders were screened with a variety of methods including conventional karyotype, microsatellite segregation analysis, subtelomeric multiplex ligation-dependent probe amplification) and whole-genome array-based comparative genome hybridisation. Causative abnormalities were present in 42.2% (19/45) of the samples, and 27.8% (10/36) of the patients with normal conventional karyotype carried submicroscopic imbalances. Our results include a wide variety of imbalances and point to novel chromosomal regions associated with craniosynostosis. The high incidence of pure duplications or trisomies suggests that these are important mechanisms in craniosynostosis, particularly in cases involving the metopic suture.

Brain structure and symptom dimension relationships in obsessive-compulsive disorder: A voxel-based morphometry study

Background: Obsessive-compulsive disorder (OCD) is a clinically heterogenous disorder characterized by temporally stable symptom dimensions. Past inconsistent results from structural neuroimaging studies of OCD may have resulted from the effects of these specific symptom dimensions as well as other socio-demographic and clinical variables upon gray matter (GM) volume. Methods: GM volume was measured in 25 adult OCD patients and 20 adult healthy controls using voxel-based morphometry (VBM), controlling for age and total brain GM volume. Univariate and multivariate regression analyses were carried out between regions of GM difference and age, age of onset, medication load, OCD severity, depression severity, and separate symptom dimension scores. Results: Significant GM volumetric differences in OCD patients relative to controls were found in dorsal cortical regions, including bilateral BA6, BA46, BA9 and right BA8 (controls > patients), and bilateral midbrain (patients > controls). Stepwise regression analyses revealed highly significant relationships between greater total OCD symptom severity and smaller GM volumes in dorsal cortical regions and larger GM volumes in bilateral midbrain. Greater age was independently associated with smaller GM volumes in right BA6, left BA9, left BA46 and larger GM volumes in right midbrain. Greater washing symptom severity was independently associated with smaller GM volume in right BA6, while there was a trend association between greater hoarding symptom severity and lower GM volume in left BA6. Limitations: The sample was relatively small to examine the relationship between symptom scores and GM volumes. Multiple patients were taking medication and had comorbid disorders. Conclusions: These analyses suggest dorsal prefrontal cortical and bilateral midbrain GM abnormalities in OCD that appear to be primarily driven by the effects of total OCD symptom severity. The results regarding the relationship between GM volumes and symptom dimension scores require examination in larger samples. (C) 2008 Elsevier B.V. All rights reserved.

Abnormal corpus callosum myelination in pediatric bipolar patients

Background: Decreased signal intensity in the corpus callosum, reported in adult bipolar disorder patients, has been regarded as an indicator of abnormalities in myelination. Here we compared the callosal signal intensity of children and adolescents with bipolar disorder to that of matched healthy subjects, to investigate the hypothesis that callosal myelination is abnormal in pediatric bipolar patients. Methods: Children and adolescents with DSM-lV bipolar disorder (n=16, mean age +/- S.D. = 15.5 +/- 3.4 y) and matched healthy comparison subjects (n=21, mean age +/- S.D.=16.9 3.8 y) underwent a 1.5 T MRI brain scan. Corpus callosuin signal intensity was measured using an Apple Power Mac G4 running NIH Image 1.62 software. Results: Bipolar children and adolescents had significantly lower corpus callosum signal intensity for all callosal sub-regions (genu, anterior body, posterior body, isthmus and splenium) compared to healthy subjects (ANCOVA, all p < 0.05, age and gender as covariates). Limitations: Relatively small sample size. Conclusions: Abnormalities in corpus callosum, probably due to altered myelination during neurodevelopment, may play a role in the pathophysiology of bipolar disorder among children and adolescents. (c) 2007 Elsevier B.V All rights reserved.

Exercise training prevents beta-adrenergic hyperactivity-induced myocardial hypertrophy and lesions

Background: Sustained beta-adrenoreceptor activation promotes cardiac hypertrophy and cellular injury. Aims: To evaluate the cardioprotective effect of exercise on damage induced by beta-adrenergic hyperactivity. Methods: Male Wistar rats were randomised into four groups (n=8 per group): sedentary non-treated control (C), sedentary treated with isoproterenol 0.3 mg/kg/day administered subcutaneously for 8 days (1), exercised non-treated (E) and exercised plus isoproterenol administered during the last eight days of exercise (IE). Exercised animals ran on a treadmill for 1 h daily 6 times a week for 13 weeks. Results: Isoproterenol caused increases in left ventricle (LV) wet and dry weight/body weight ratio, LV water content and cardiomyocyte transverse diameter. Additionally, isoproterenol induced severe cellular lesions, necrosis, and apoptosis, increased collagen content and reduced capillary and fibre fractional areas. Notably, all of these abnormalities were completely prevented by exercise. Conclusion: Our data have demonstrated that complete cardioprotection is possible through exercise training; by preventing p-adrenergic hyperactivity-induced cardiac hypertrophy and structural injury. (c) 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.