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.

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.

Comparison of HRT-3 glaucoma probability score and subjective stereophotograph assessment for prediction of progression in glaucoma

PURPOSE. To assess whether baseline Glaucoma Probability Score (GPS; HRT-3; Heidelberg Engineering, Dossenheim, Germany) results are predictive of progression in patients with suspected glaucoma. The GPS is a new feature of the confocal scanning laser ophthalmoscope that generates an operator-independent, three-dimensional model of the optic nerve head and gives a score for the probability that this model is consistent with glaucomatous damage. METHODS. The study included 223 patients with suspected glaucoma during an average follow-up of 63.3 months. Included subjects had a suspect optic disc appearance and/or elevated intraocular pressure, but normal visual fields. Conversion was defined as development of either repeatable abnormal visual fields or glaucomatous deterioration in the appearance of the optic disc during the study period. The association between baseline GPS and conversion was investigated by Cox regression models. RESULTS. Fifty-four (24.2%) eyes converted. In multivariate models, both higher values of GPS global and subjective stereophotograph assessment ( larger cup-disc ratio and glaucomatous grading) were predictive of conversion: adjusted hazard ratios (95% CI): 1.31 (1.15 - 1.50) per 0.1 higher global GPS, 1.34 (1.12 - 1.62) per 0.1 higher CDR, and 2.34 (1.22 - 4.47) for abnormal grading, respectively. No significant differences ( P > 0.05 for all comparisons) were found between the c-index values ( equivalent to area under ROC curve) for the multivariate models (0.732, 0.705, and 0.699, respectively). CONCLUSIONS. GPS values were predictive of conversion in our population of patients with suspected glaucoma. Further, they performed as well as subjective assessment of the optic disc. These results suggest that GPS could potentially replace stereophotograph as a tool for estimating the likelihood of conversion to glaucoma.

Neurosyphilis in HIV-infected patients: Clinical manifestations, serum venereal disease research laboratory titers, and associated factors to symptomatic neurosyphilis

Goal: To describe clinical and laboratory features of human immunodeficiency infection (HIV)-infected patients with neurosyphilis. Study Design: Retrospective study of 27 consecutive cases of HIV-infected patients with a positive Venereal Disease Research Laboratory (VDRL) in cerebrospinal fluid (CSF). Results: Median of age was 36 years and 89% were men. Ten (37%) patients had previous nonneurologic syphilis treatment. At the time of neurosyphilis diagnosis, 10 (37%) patients had early syphilis, and 6 of them were neurologically asymptomatic. Nine (33%) patients had symptomatic neurosyphilis. Twenty-six (96%) patients were classified with early neurosyphilis. The medians of serum VDRL and CD4(+) T cell counts were 1:128 and 182 cell/mu L, respectively. Twenty five (93%) patients presented serum VDRL titers >= 1:16. Five of 6 patients with early syphilis and asymptomatic neurosyphilis, presented serum VDRL >= 1:16. Symptomatic patients showed lower CD4(+) T cell counts (59 cell/mu L vs. 208 cell/mu L, P = 0.03) and higher protein concentration on CSF (118 mg/dL vs. 39 mg/dL, P <0.001) than asymptomatic patients. Conclusions: Most patients had early and asymptomatic neurosyphilis, and more than one third had early syphilis. Patients with symptomatic neurosyphilis showed lower CD4(+) T cell counts and higher protein concentration on CSF than those asymptomatic. Most patients had serum VDRL titers >= 1:16, regardless of syphilis stage.

Alagille syndrome and nephroblastoma: Unusual coincidence of two rare disorders

Alagille syndrome is a rare developmental disorder combining bile duct paucity, congenital cardiopathy, facial dysmorphy, vertebrae defects, and ocular abnormalities; and frequent renal abnormalities. It does not usually predispose to malignancies. Nephroblastoma has been observed in many developmental disorders, but never in Alagille syndrome. We report two original cases of nephroblastoma associated to Alagille syndrome. We identified a new V136G JAG1 missense mutation in one patient and a constitutional deletion of 20p12 in the other. In one nephroblastoma an additional somatic 1p36 deletion was present. The link between Alagille syndrome, JAG1 alterations and nephroblastoma is discussed.

Altered endothelial function following the Fontan procedure

Objective: Thrombosis has been widely described after the Fontan procedure. The vascular endothelium plays a central role in the control of coagulation and fibrinolysis. The aim of this study was to investigate if patients undergoing a modified Fontan procedure have impaired endothelial function and fibrinolysis in the late postoperative course. Patients and methods: We compared 23 patients aged from 7 to 26 years with age-matched healthy volunteers, collecting blood samples prior to and following standardized venous occlusion testing. Plasma levels of von Willebrand factor antigen, tissue-type plasminogen activator antigen, plasminogen activator inhibitor-1, and D-dimer were measured with enzyme-linked immunosorbent assay. Results: We found increased plasma levels of von Willebrand factor antigen in patients when compared to controls (p = 0.003). At the basal condition, concentrations of tissue-type plasminogen activator antigen and plasminogen activator inhibitor-1 antigen in the plasma, as well as their activity, were not significantly different between patients and controls. Following venous occlusion, concentrations of tissue-type plasminogen activator antigen in the plasma were significantly increased both in patients and controls, compared to pre-occlusion values. D-dimer was within the reference range. Multivariate discriminant analysis differentiated patients and their controls on the basis of differences for plasminogen activator inhibitor-1 and von Willebrand factor antigen (p = 0.0016). Conclusions: Our data suggest that patients with the Fontan circulation may have endothelial dysfunction, as indicated by raised levels of von Willebrand factor. Fibrinolysis seems to be relatively preserved, as suggested by appropriate response to venous occlusion.

Comparison of renal transplantation outcomes in children with and without bladder dysfunction. A customized approach equals the difference

Purpose: We examined the development of urological abnormalities in a group of pediatric renal transplant recipients. Materials and Methods: We reviewed 211 patients younger than 19 years who underwent 226 renal transplants. Three groups of patients were studied-136 children with end stage renal disease due to a nonurological cause (group 1), 56 children with a urological disorder but with an adequate bladder (group 2a) and 19 children with lower urinary tract dysfunction and/or inadequate bladder drainage (group 2b). A total of 15 children in group 2b underwent bladder augmentation (ureterocystoplasty in 6, enterocystoplasty in 9), 2 underwent continent urinary diversion, 1 underwent autoaugmentation and 1 underwent a Mitrofanoff procedure at the bladder for easier drainage. Kidney transplantation was performed in the classic manner by extraperitoneal access, and whenever possible the ureter was reimplanted using an antireflux procedure. Results: At a mean followup of 75 months 13 children had died, 59 grafts were lost and 15 children had received a second transplant. Two patients in group 2a required a complementary urological procedure to preserve renal function (1 enterocystoplasty, 1 vesicostomy). A total of 12 major surgical complications occurred in 226 kidney transplants (5.3%), with a similar incidence in all groups. The overall graft survival at 5 years was 75%, 74% and 84%, respectively, in groups 1, 2a and 2b. Conclusions: With individualized treatment children with severely inferior lower urinary tract function may undergo renal transplantation with a safe and adequate outcome.

Evaluation of renal function in leprosy: a study of 59 consecutive patients

Background. Renal abnormalities in leprosy have been largely described in medical literature, but there are few studies evaluating renal function in these patients. Methods. This is a cross-sectional study in 59 consecutive paucibacillary (PB) and multibacillary (MB) leprosy patients. Glomerular filtration rate (GFR) was estimated by simplified-MDRD formula. Microalbuminuria was determined by 24 h urine collection. Urinary acidification capacity was measured after water deprivation and acid-loading with CaCl2. Urinary concentration capacity was evaluated after desmopressin acetate administration, using the urinary to plasma osmolality (U/P-osm) ratio. All parameters except microalbuminuria were measured in a control group of 18 healthy volunteers. Results. Age and gender were similar between leprosy (MB or PB) and control groups. GFR <= 80 ml/min/1.73 m(2) was observed in 50% of the leprosy patients. GFR and U/P-osm in leprosy patients were significantly lower than in controls (P < 0.001). Urinary acidification defect was found in 32% of PB and in 29% of MB patients and urinary concentrating ability was abnormal in 83% of PB and 85% of MB patients. Microalbuminuria was found in 4 patients (8.5%), leukocyturia was found in 13 (22%) and haematuria was present in 16 patients (27%). Plasma creatinine (P-cr) > 1.2 mg/dl was observed in 17.9% of MB patients and in none of the controls (P = 0.020). A negative correlation was observed between GFR and time of treatment (r = -0.339; P = 0.002). Age and time of treatment were independent risk factors for GFR <= 80 ml/min/1.73 m(2) in multivariate analysis. Conclusions. Asymptomatic GFR changes and renal tubular dysfunction, including urine concentration defect and impaired acidifying mechanisms, can be caused by leprosy on specific treatment and without any reaction episodes.

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p. Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Background: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. Objectives: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. Subjects and methods: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 mu g/kg BID. Results: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. Conclusion: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.