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.

Haze Development After Photorefractive Keratectomy: Mechanical vs Ethanol Epithelial Removal in Rabbits

PURPOSE: To compare mechanical and ethanol epithelial removal with respect to myofibroblast development and haze formation after photorefractive keratectomy (PRK). METHODS: Seventeen rabbits underwent mechanical or ethanol debridement, and the opposite eye of each rabbit served as an unwounded control. In both groups, the epithelium was removed with a spatula and discarded. A -9.00-diopter PRK was performed in each eye. The level of haze in each cornea at 4 weeks was graded at the slit-lamp microscope according to the Fantes scale. Myofibroblast generation was detected with immunocytochemistry for alpha-smooth muscle actin (alpha-SMA) and cells were quantitatively analyzed. RESULTS: No difference was noted between the two groups in alpha-SMA + myofibroblasts 4 weeks after surgery (43.6 +/- 2.0/400X field and 45.7 +/- 4.8/400X field in ethanol and mechanical groups, respectively) (P=.10). A slight difference was noted but did not reach statistical significance with regard to stromal haze between ethanol and mechanical groups (2.0 +/- 0.5 and 2.3 +/- 0.4, respectively, P=.063). The ethanol and mechanical groups were statistically different when compared to controls regarding stromal haze and alpha-SMA+ cells (P <.0001 for all comparisons). CONCLUSIONS:No difference was noted in clinical haze or myofibroblast generation between corneas that had PRK with mechanical,or ethanol epithelial debridement. [J Refract Surg., 2008;24:923-927.]

Benzylglucosinolate, Benzylisothiocyanate, and Myrosinase Activity in Papaya Fruit during Development and Ripening

Papaya is a climacteric fruit that has high amounts of benzylglucosinolates (BG) and benzylisothiocyanates (BITC), but information regarding levels of BG or BITC during fruit development and ripening is limited. Because BG and BITC are compounds of importance from both a nutritional and a crop yield standpoint, the aim of this work was to access data on the distribution and changes of BG and BITC levels during fruit development and ripening. BG and BITC levels were quantified in peel, pulp, and seeds of papaya fruit. Volatile BITC was also verified in the internal cavity of the fruit during ripening. The influence of the ethylene in BG and BITC levels and mirosinase activity was tested by exposing mature green fruits to ethylene and 1-methylcyclopropene (1-MCP). The highest BG levels were detected in seeds, followed by the peel and pulp being decreased in all tissues during fruit development. Similarly, the levels of BITC were much higher in the seeds than the peel and pulp. The levels of BG for control and ethylene-treated fruit were very similar, increasing in the pulp and peel during late ripening but not changing significantly in seeds. On the other hand, fruit exposed to 1-MCP showed a decrease in BG amount in the pulp and accumulation in seed. The treatments did not result in clear differences regarding the amount of BITC in the pulp and peel of the fruit. According to the results, ethylene does not have a clear effect on BITC accumulation in ripening papaya fruit. The fact that BG levels in the pulp did not decrease during ripening, regardless of the treatment employed, and that papaya is consumed mainly as fresh fruit, speaks in favor of this fruit as a good dietary source for glucosinolate and isothiocyanates.

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.

Chronic exposure to ambient levels of urban particles affects mouse lung development

Rationale- Chronic exposure to air pollution has been associated with adverse effects on children`s lung growth. Objectives: We analyzed the effects of chronic exposure to urban levels of particulate matter (PM) on selected phases of mouse lung development. Methods: The exposure occurred in two open-top chambers (filtered and nonfiltered) placed 20 m from a street with heavy traffic in Sao Paulo, 24 hours/day for 8 months. There was a significant reduction of the levels of PM(2.5) inside the filtered chamber (filtered = 2.9 +/- 3.0 mu g/m(3), nonfiltered = 16.8 +/- 8.3 mu g/m(3); P = 0.001). At this exposure site, vehicular sources are the major components of PM(2.5) (PM <= 2.5 mu m). Exposure of the parental generation in the two chambers occurred from the 10th to the 120th days of life. After mating and birth of offspring, a crossover of mothers and pups occurred within the chambers, resulting in four groups of pups: nonexposed, prenatal, postnatal, and pre+postnatal. Offspring were killed at the age of 15 (n = 42) and 90 (n = 35) days; lungs were analyzed by morphometry for surface to volume ratio (as an estimator of alveolization). Pressure-volume curves were performed in the older groups, using a 20-ml plethysmograph. Measurements and Main Results: Mice exposed to PM(2.5) pre+postnatally presented a smaller surface to volume ratio when compared with nonexposed animals (P = 0.036). The pre+postnatal group presented reduced inspiratory and expiratory volumes at higher levels of transpulmonary pressure (P = 0.001). There were no differences among prenatal and postnatal exposure and nonexposed animals. Conclusions: Our data provide anatomical and functional support to the concept that chronic exposure to urban PM affects lung growth.

The development of a rat model of erectile dysfunction after radical prostatectomy: preliminary findings

To develop a rat model of erectile dysfunction (ED) after cavernous nerve injury. Given the great similarity between the anatomical structure of the cavernous nerve in rats and humans, 24 rats underwent dissections and the cavernous nerves were identified with the aid of an operating microscope. Then the rats were randomized into two groups: sham-operated controls and a bilateral cavernous nerve section group. At 3 months after surgery, the rats were evaluated for their response to an apomorphine challenge. The erectile response after an apomorphine challenge was normal in all the control rats, while there were no erections in the bilateral injured group. The rat major autonomic ganglion and its cavernous nerve can be identified with the aid of a microscope. Rats are inexpensive and easy to handle, thus a good animal for developing an ED model of cavernous nerve injury. In the present study, the rats with cavernous nerve injury lost erectile capacity in a reliable and reproducible fashion. Because of the great similarity between the cavernous nerve of rats and humans, one may consider this technique as a reliable experimental model for studying ED after radical prostatectomy.

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.

Relationship of adhesion molecules expression with epithelial differentiation markers during fetal skin development

Background: Cadherins and integrins are important for maintenance of tissue integrity and in signal transduction during skin development. Distribution of these molecules in human skin development was investigated and associated with markers of differentiation, cytokeratins (CK) and involucrin (INV). Methods: Using immunohistochemistry expression of E- and P-cadherins, integrins beta-1 and -4, CK10, CK14 and INV was assessed in skin fragments of 10 human fetuses (gestational weeks ranged from 4 to 24, all weighing up to 500 g). Results: At initial phases of development, integrins beta-1 and -4 and E- and P-cadherins were present on epithelial cell membranes in all layers. CK14 and CK10 were expressed in all epithelial layers and INV weakly detected in the superficial layer. In more advanced stages, integrins were detected in all layers, but a marked polarized expression was seen in basal layer. E-cadherin was detected in all layers, but the cornified stratum and P-cadherin were observed in the lower layers. CK14 was expressed in basal layer, CK10 in suprabasal stratum and INV was observed in cornified layer. Conclusions: Cadherins and integrins are essential for skin development, being spatially and temporally regulated. Their expression is related with the expression of maturation markers of the epidermis.

Language impairment in euthymic, elderly patients with bipolar disorder but no dementia

Background: Neurocognitive impairment is known to occur in euthymic bipolar patients, but language alterations have not been thoroughly investigated. The aim of this study is to examine the performance in language tests of a sample of elderly patients with bipolar disorder. Methods: We studied 33 eurthymic elderly patients with bipolar disorder but no dementia and 33 healthy individuals, matched for age and education, who were compared in terms of their CAMCOG global score and its subitems. Results: The scores obtained in language-related abilities for patients and controls, respectively, were: language (total): 27.3 (1) and 28.5 (1), p < 0.0001)comprehension: 8.6 (0.5) and 8.9 (0.3), p = 0.006; production: 18.7 (1) and 19.6 (0.9), p = < 0.0001; abstraction: 6.8 (1.1) and 7.3 (0.7), p = 0.016; verbal fluency: 16.3 (4.3) and 19.6 (4.1), p = 0.003. Conclusion: A mild but significant impairment in language-related ability scores was detected when comparing patients and controls.

Association between personality disorder and violent behavior pattern

Personality disorders are associated with criminality and antisocial and borderline personalities as strong predictors of violence. Nevertheless antisocial patients show more instrumental violence, while borderline patients more emotional violence. We surveilled medical records of a personality disorder facility, searching data of aggression and crimes against property among 11 patients with antisocial personality disorder and 19 borderline personality disorder. We found that there are differences regarding engagement in violence and lawbreaking according to the personality disorder: antisocial patients statistically engage more in crimes against property than the borderline patients, and more in this kind of crime than in aggression, whilst borderline patients show a tendency to engage more in episodes of aggression and physical violence than antisocial patients, and less in crimes against property. We conclude that the distinct personality leads to a distinct pattern of crimes and violence: antisocial patients are c old and get more involved in crimes requiring more detailed planning, whilst borderline patients are impulsive and engage in explosive episodes of physical violence. Further studies on the association among personality disorder, behavior pattern and violence type may be useful for both treatment and criminal profiling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

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.

Temperament and character traits in patients with bipolar disorder and associations with comorbid alcoholism or anxiety disorders

Temperament and character traits may determine differences in clinical presentations and outcome of bipolar disorder. We compared personality traits in bipolar patients and healthy individuals using the Temperament and Character Inventory (TCI) and sought to verify whether comorbidity with alcoholism or anxiety disorders is associated with specific personality traits. Seventy-three DSM-IV bipolar patients were compared to 63 healthy individuals using the TCI. In a second step, the bipolar sample was subgrouped according to the presence of psychiatric comorbidity (alcoholism, n = 10; anxiety disorders; n = 23; alcoholism plus anxiety disorders, n = 21; no comorbidity, n = 19). Bipolar patients scored statistically higher than the healthy individuals on novelty seeking, harm avoidance and self-transcendence and lower on self-directedness and cooperativeness. Bipolar patients with only comorbid alcoholism scored statistically lower than bipolar patients without any comorbidity on persistence. Bipolar patients with only comorbid anxiety disorders scored statistically higher on harm avoidance and lower on self-directedness than bipolar patients without any comorbidity. Limitations of this study include the cross-sectional design and the small sample size, specifically in the analysis of the subgroups. However, our results suggest that bipolar patients exhibit a different personality structure than healthy individuals and that presence of psychiatric comorbidity in bipolar disorder is associated with specific personality traits. These findings suggest that personality, at least to some extent, mediates the comorbidity phenomena in bipolar disorder. (C) 2007 Elsevier Ltd. All rights reserved.

Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder

Declarative memory impairments are common in patients with bipolar illness, suggesting underlying hippocampal pathology. However, hippocampal volume deficits are rarely observed in bipolar disorder. Here we used surface-based anatomic mapping to examine hippocampal anatomy in bipolar patients treated with lithium relative to matched control subjects and unmedicated patients with bipolar disorder. High-resolution brain magnetic resonance images were acquired from 33 patients with bipolar disorder ( 21 treated with lithium and 12 unmedicated), and 62 demographically matched healthy control subjects. Three-dimensional parametric mesh models were created from manual tracings of the hippocampal formation. Total hippocampal volume was significantly larger in lithium-treated bipolar patients compared with healthy controls (by 10.3%; p=0.001) and unmedicated bipolar patients ( by 13.9%; p=0.003). Statistical mapping results, confirmed by permutation testing, revealed localized deficits in the right hippocampus, in regions corresponding primarily to cornu ammonis vertical bar subfields, in unmedicated bipolar patients, as compared to both normal controls (p=0.01), and in lithium-treated bipolar patients (p=0.03). These findings demonstrate the sensitivity of these anatomic mapping methods for detecting subtle alterations in hippocampal structure in bipolar disorder. The observed reduction in subregions of the hippocampus in unmedicated bipolar patients suggests a possible neural correlate for memory deficits frequently reported in this illness. Moreover, increased hippocampal volume in lithium-treated bipolar patients may reflect postulated neurotrophic effects of this agent, a possibility warranting further study in longitudinal investigations.

Family environment patterns in families with bipolar children

Background: We studied the characteristics of family functioning in bipolar children and healthy comparison children. We hypothesized that the family environment of bipolar children would show greater levels of dysfunction as measured by the Family Environment Scale (FES). Methods: We compared the family functioning of 36 families that included a child with DSM-IV bipolar disorder versus 29 comparison families that included only healthy children. All subjects and their parents were assessed with the K-SADS-PL interview. The parents completed the FES to assess their current family functioning. Multivariate analysis of variance was used to compare the family environment of families with and without offspring with bipolar disorder. Results: Parents of bipolar children reported lower levels of family cohesion (p<0.001), expressiveness (p=0.005), active-recreational orientation (p<0.001), intellectual-cultural orientation (p=0.04) and higher levels of conflict (p<0.001) compared to parents with no bipolar children. Secondary analyses within the bipolar group revealed lower levels of organization (p=0.03 1) and cohesion (p=0.014) in families where a parent had a history of mood disorders compared to families where parents had no history of mood disorders. Length of illness in the affected child was inversely associated with family cohesion (r=-0.47, p=0.004). Limitations: Due to the case-control design of the study, we cannot comment on the development of these family problems or attribute their cause specifically to child bipolar disorder. Conclusion: Families with bipolar children show dysfunctional patterns related to interpersonal interactions and personal growth. A distressed family environment should be addressed when treating children with bipolar disorder. (C) 2007 Elsevier B.V. All rights reserved.

Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study

Objective To investigate whether the cox-2 inhibitor celecoxib has antidepressant effects in bipolar disorder (BD) patients during depressive or mixed phases. Methods We studied 28 DSM-IV BD patients who were experiencing a depressive or mixed episode and were on a stable dose of a mood stabilizer or atypical antipsychotic medication. Subjects were randomized to receive 6 weeks of double-blind placebo or celecoxib (400 mg/day) treatment. Current mood stabilizer or antipsychotic medication remained at the same doses during the trial. Results Intention-to-treat analysis showed that the patients receiving celecoxib had lower Hamilton Depression Rating Scale (HamD) scores after 1 week of treatment compared to the patients receiving placebo, but this difference was not statistically significant (p=0.09). The improvement in the first week of treatment was statistically significant when the analysis included only the subjects who completed the full 6-week trial (p=0.03). The two groups did not differ significantly on depressive or manic symptoms from the second week until the end of the trial. Celecoxib was well tolerated with the exception of two subjects who dropped out of the study due to rash. Conclusions Our findings suggest that adjunctive treatment with celecoxib may produce a rapid-onset antidepressant effect in BD patients experiencing depressive or mixed episodes. Copyright (C) 2008 John Wiley & Sons, Ltd.