Phenotype-genotype analysis of cryopyrin-associated periodic syndromes (CAPS): Description of a rare non-exon 3 and a novel CIAS1 missense mutation

We describe in this paper the phenotype-genotype analysis of a Brazilian cohort of patients with cryopyrin-associated periodic syndromes (CAPS). Patient 1 presented with an urticarial rash and recurrent fever exacerbated by cold weather, arthritis, and anterior uveitis, thus, receiving a clinical diagnosis of familial cold autoinflammatory syndrome. CIAS1 sequencing identified the T436I mutation, previously associated to a clinical phenotype of chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease. Patient 2 developed a papular exanthema with daily fever shortly after birth, frontal bossing, patellae enlargement, and cognitive and motor impairments. Sequencing identified the exceedingly rare G755R CIAS1 mutation in exon 4. Patient 3 developed skin rash and articular symptoms 6 h after birth, followed by aseptic meningitis. He was found to have the novel C148Y missense mutation in CIAS1. This report expands the spectrum of CIAS1 mutations associated to clinical disease, suggests that the same mutation can be associated with different clinical syndromes, and supports the evidence that CAPS patients should always be screened for mutations outside exon 3.

A population-based morphometric MRI study in patients with first-episode psychotic bipolar disorder: comparison with geographically matched healthy controls and major depressive disorder subjects

Objectives: Many morphometric magnetic resonance imaging (MRI) studies that have investigated the presence of gray matter (GM) volume abnormalities associated with the diagnosis of bipolar disorder (BD) have reported conflicting findings. None of these studies has compared patients with recent-onset psychotic BD with asymptomatic controls selected from exactly the same environment using epidemiological methods, or has directly contrasted BD patients against subjects with first-onset psychotic major depressive disorder (MDD). We examined structural brain differences between (i) BD (type I) subjects and MDD subjects with psychotic features in their first contact with the healthcare system in Brazil, and (ii) these two mood disorder groups relative to a sample of geographically matched asymptomatic controls. Methods: A total of 26 BD subjects, 20 subjects with MDD, and 94 healthy controls were examined using either of two identical MRI scanners and acquisition protocols. Diagnoses were based on DSM-IV criteria and confirmed one year after brain scanning. Image processing was conducted using voxel-based morphometry. Results: The BD group showed increased volume of the right dorsal anterior cingulate cortex relative to controls, while the MDD subjects exhibited bilateral foci GM deficits in the dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons). Direct comparison between BD and MDD patients showed a focus of GM reduction in the right-sided dorsolateral prefrontal cortex (p < 0.05, corrected for multiple comparisons) and a trend (p < 0.10, corrected) toward left-sided GM deficits in the dorsolateral prefrontal cortex of MDD patients. When analyses were repeated with scanner site as a confounding covariate the finding of increased right anterior cingulate volumes in BD patients relative to controls remained statistically significant (p = 0.01, corrected for multiple comparisons). Conclusions: These findings reinforce the view that there are important pathophysiological distinctions between BD and MDD, and indicate that subtle dorsal anterior cingulate abnormalities may be relevant to the pathophysiology of BD.

Lower N-Acetyl-Aspartate Levels in Prefrontal Cortices in Pediatric Bipolar Disorder: A (1)H Magnetic Resonance Spectroscopy Study

Objective: The few studies applying single-voxel(1)H spectroscopy in children and adolescents with bipolar disorder (BD) have reported low N-acetyl-aspartate (NAA) levels in the dorsolateral prefrontal cortex (DLPFC), and high myo-inositol / phosphocreatine plus creatine (PCr+Cr) ratios in the anterior cingulate. The aim of this study was to evaluate NAA, glycerophosphocholine plus phosphocholine (GPC+PC) and PCr+Cr in various frontal cortical areas in children and adolescents with BD. We hypothesized that NAA levels within the prefrontal cortex are lower in BD patients than in healthy controls, indicating neurodevelopmental alterations in the former. Method: We studied 43 pediatric patients with DSM-IV BD (19 female, mean age 13.2 +/- 2.9 years) and 38 healthy controls (79 female, mean age 13.9 +/- 2.7 years). We conducted multivoxel in vivo (1)H spectroscopy measurements at 1.5 Tesla using a long echo time of 272 ms to obtain bilateral metabolite levels from the medial prefrontal cortex (MPFC), DLPFC (white and gray matter), cingulate (anterior and posterior), and occipital lobes. We used the nonparametric Mann-Whitney U test to compare neurochemical levels between groups. Results: In pediatric BD patients, NAA and GPC+PC levels in the bilateral MPFC, and PCr+Cr levels in the left MPFC were lower than those seen in the controls. In the left DLPFC white matter, levels of NAA and PCr+Cr were also lower in BD patients than in controls. Conclusions: Lower NAA and PCr+Cr levels in the PFC of children and adolescents with BD may be indicative of abnormal dendritic arborization and neuropil, suggesting neurodevelopmental abnormalities. J. Am. Acad. Child Adolesc. Psychiatry, 2011;50(1):85-94.

The frontal assessment battery (FAB) reveals neurocognitive dysfunction in substance-dependent individuals in distinct executive domains: Abstract reasoning, motor programming, and cognitive flexibility

Substance-dependence is highly associated with executive cognitive function (ECF) impairments. However. considering that it is difficult to assess ECF clinically, the aim of the present study was to examine the feasibility of a brief neuropsychological tool (the Frontal Assessment Battery FAB) to detect specific ECF impairments in a sample of substance-dependent individuals (SDI). Sixty-two subjects participated in this study. Thirty DSM-IV-diagnosed SDI, after 2 weeks of abstinence, and 32 healthy individuals (control group) were evaluated with FAD and other ECF-related tasks: digits forward (DF), digits backward (DB), Stroop Color Word Test (SCWT), and Wisconsin Card Sorting Test (WCST). SDI did not differ from the control group on sociodemographic variables or IQ. However, SDI performed below the controls in OF, DB, and FAB. The SDI were cognitively impaired in 3 of the 6 cognitive domains assessed by the FAB: abstract reasoning, motor programming, and cognitive flexibility. The FAB correlated with DF, SCWT, and WCST. In addition, some neuropsychological measures were correlated with the amount of alcohol, cannabis, and cocaine use. In conclusion, SDI performed more poorly than the comparison group on the FAB and the FAB`s results were associated with other ECF-related tasks. The results suggested a negative impact of alcohol, cannabis, and cocaine use on the ECF. The FAB may be useful in assisting professionals as an instrument to screen for ECF-related deficits in SDI. (C) 2010 Elsevier Ltd. All rights reserved.

Treatment of Resistant Obsessive-Compulsive Disorder With Ventral Capsular/Ventral Striatal Gamma Capsulotomy: A Pilot Prospective Study

A subgroup of obsessive-compulsive disorder (OCD) patients remains refractory to conventional treatments. For them, a new stereotactic radiosurgery has been recently developed: the ventral capsular/ventral striatal (VC/VS) gamma capsulotomy. The authors aim to report efficacy and adverse events of VC/VS gamma capsulotomy. Five refractory OCD patients were selected. The authors assessed OCD, anxiety and depressive symptoms, and side effects pre- and postoperatively. Three patients (60%) met response criteria 48 months after surgery. Adverse effects were episodic and transient. Ventral capsular/ventral striatal gamma capsulotomy holds therapeutic promise, with few adverse effects. (The Journal of Neuropsychiatry and Clinical Neurosciences 2009; 21:381-392)

Cognitive performance is related to cortical grey matter volumes in early stages of schizophrenia: A population-based study of first-episode psychosis

Background: Neuropsychological deficits have been reported in association with first-episode psychosis (FEP). Reductions in grey matter (GM) volumes have been documented in FEP subjects compared to healthy controls. However, the possible inter-relationship between the findings of those two lines of research has been scarcely investigated. Objective: To investigate the relationship between neuropsychological deficits and GM volume abnormalities in a population-based sample of FEP patients compared to healthy controls from the same geographical area. Methods: FEP patients (n = 88) and control subjects (n = 86) were evaluated by neuropsychological assessment (Controlled Oral Word Association Test, forward and backward digit span tests) and magnetic resonance imaging using voxel-based morphometry. Results: Single-group analyses showed that prefrontal and temporo-parietal GM volumes correlated significantly (p < 0.05, corrected) with cognitive performance in FEP patients. A similar pattern of direct correlations between neocortical GM volumes and cognitive impairment was seen in the schizophrenia subgroup (n = 48). In the control group, cognitive performance was directly correlated with GM volume in the right dorsal anterior cingulate cortex and inversely correlated with parahippocampal gyral volumes bilaterally. Interaction analyses with ""group status"" as a predictor variable showed significantly greater positive correlation within the left inferior prefrontal cortex (BA46) in the FEP group relative to controls, and significantly greater negative correlation within the left parahippocampal gyrus in the control group relative to FEP patients. Conclusion: Our results indicate that cognitive deficits are directly related to brain volume abnormalities in frontal and temporo-parietal cortices in FEP subjects, most specifically in inferior portions of the dorsolateral prefrontal cortex. (C) 2009 Elsevier B.V. All rights reserved.

Stereologic investigation of the posterior part of the hippocampus in schizophrenia

Structural magnetic resonance imaging and postmortem studies showed volume loss in the hippocampus in schizophrenia. The noted tissue reduction in the posterior section suggests that some cellular subfractions within this structure might be reduced in schizophrenia. To address this, we investigated numbers and densities of neurons, oligodendrocytes and astrocytes in the posterior hippocampal subregions in postmortem brains from ten patients with schizophrenia and ten matched controls using design-based stereology performed on Nissl-stained sections. Compared to the controls, the patients with schizophrenia showed a significant decrease in the mean number of oligodendrocytes in the left and right CA4. This is the first finding of reduced numbers of oligodendrocytes in CA4 of the posterior part of the hippocampus in schizophrenia. Our results are in line with earlier findings in the literature concerning decreased numbers of oligodendrocytes in the prefrontal cortex in schizophrenia. Our results may indicate disturbed connectivity of the CA4 of the posterior part of the hippocampus in schizophrenia and, thus, contribute to the growing number of studies showing the involvement of posterior hippocampal pathology in the pathophysiology of schizophrenia.

Association between symptom severity and internal capsule volume in obsessive-compulsive disorder

Neurobiological models support an involvement of white matter tracts in the pathophysiology of obsessive-compulsive disorder (OCD), but there has been little systematic evaluation of white matter volumes in OCD using magnetic resonance imaging (MRI). We investigated potential differences in the volume of the cingulum bundle (CB) and anterior limb of internal capsule (ALIC) in OCD patients (n = 19) relative to asymptomatic control subjects (n = 15). White matter volumes were assessed using a 1.5T MRI scanner. Between-group comparisons were carried out after spatial normalization and image segmentation using optimized voxel-based morphometry. Correlations between regional white matter volumes in OCD subjects and symptom severity ratings were also investigated. We found significant global white matter reductions in OCD patients compared to control subjects. The voxel-based search for regional abnormalities (with covariance for total white matter volumes) showed no specific white matter volume deficits in brain portions predicted a priori to be affected in OCD (CB and ALIC). However, large clusters of significant positive correlation with OCD severity scores were found bilaterally on the ALIC. These findings provide evidence of OCD-related ALIC abnormalities and suggest a connectivity dysfunction within frontal-striatal-thalamic-cortical circuits. Further studies are warranted to better define the role of such white matter alterations in the pathophysiology of OCD, and may provide clues for a more effectively targeting of neurosurgical treatments for OCD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Gamma ventral capsulotomy for treatment of resistant obsessive-compulsive disorder: A structural MRI pilot prospective study

Objective: The purpose of this study was to investigate regional structural abnormalities in the brains of five patients with refractory obsessive-compulsive disorder (OCD) submitted to gamma ventral capsulotomy. Methods: We acquired morphometric magnetic resonance imaging (MRI) data before and after 1 year of radiosurgery using a 1.5-T MRI scanner. Images were spatially normalized and segmented using optimized voxel-based morphometry (VBM) methods. Voxelwise statistical comparisons between pre- and post-surgery MRI scans were performed using a general linear model. Findings in regions predicted a priori to show volumetric changes (orbitofrontal cortex, anterior cingulate gyrus, basal ganglia and thalamus) were reported as significant if surpassing a statistical threshold of p<0.001 (uncorrected for multiple comparisons). Results: We detected a significant regional postoperative increase in gray matter volume in the right inferior frontal gyri (Brodmann area 47, BA47) when comparing all patients pre and postoperatively. Conclusions: Our results support the current theory of frontal-striatal-thalamic-cortical (FSTC) circuitry involvement in OCD pathogenesis. Gamma ventral capsulotomy is associated with neurobiological changes in the inferior orbitofrontal cortex in refractory OCD patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Regional gray matter abnormalities in panic disorder: A voxel-based morphometry study

Although abnonnalities in brain structures involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of panic disorder (PD), relatively few studies have made use of voxel-based morphometry (VBM) magnetic resonance imaging (MRI) to determine structural brain abnormalities in PD. We have assessed gray matter volume in 19 PD patients and 20 healthy volunteers using VBM. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. A relative increase in gay matter volume was found in the left insula of PD patients compared with controls. Additional structures showing differential increases were the left superior temporal gyrus, the midbrain, and the pons. A relative gray matter deficit was found in the right anterior cingulate cortex. The insula and anterior cingulate abnormalities may be relevant to the pathophysiology of PD, since these structures participate in the evaluation process that ascribes negative emotional meaning to potentially distressing cognitive and interoceptive sensory information. The abnormal brain stem structures may be involved in the generation of panic attacks. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

A NEUROECONOMIC MODELING OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

In this paper we present a new neuroeconomics model for decision-making applied to the Attention-Deficit/Hyperactivity Disorder (ADHD). The model is based on the hypothesis that decision-making is dependent on the evaluation of expected rewards and risks assessed simultaneously in two decision spaces: the personal (PDS) and the interpersonal emotional spaces (IDS). Motivation to act is triggered by necessities identified in PDS or IDS. The adequacy of an action in fulfilling a given necessity is assumed to be dependent on the expected reward and risk evaluated in the decision spaces. Conflict generated by expected reward and risk influences the easiness (cognitive effort) and the future perspective of the decision-making. Finally, the willingness (not) to act is proposed to be a function of the expected reward (or risk), adequacy, easiness and future perspective. The two most frequent clinical forms are ADHD hyperactive (AD/HDhyp) and ADHD inattentive (AD/HDdin). AD/HDhyp behavior is hypothesized to be a consequence of experiencing high rewarding expectancies for short periods of time, low risk evaluation, and short future perspective for decision-making. AD/HDin is hypothesized to be a consequence of experiencing high rewarding expectancies for long periods of time, low risk evaluation, and long future perspective for decision-making.

Pain Relief and Functional Recovery in Patients with Complex Regional Pain Syndrome after Motor Cortex Stimulation

In addition to pain and neurovegetative symptoms, patients with severe forms of complex regional pain syndrome (CRPS) develop a broad range of symptoms, including sensory disturbances, motor impairment and dystonic posturing. While most patients respond to medical therapy, some are considered refractory and become surgical candidates. To date, the most commonly used surgical procedure for CRPS has been spinal cord stimulation. This therapy often leads to important analgesic effects, but no sensory or motor improvements. We report on 2 patients with pain related to CRPS and severe functional deficits treated with motor cortex stimulation (MCS) who not only had significant analgesic effects, but also improvements in sensory and motor symptoms. In the long term (27 and 36 months after surgery), visual analog scale pain scores were improved by 60-70% as compared to baseline. There was also a significant increase in the range of motion in the joints of the affected limbs and an improvement in allodynia, hyperpathia and hypoesthesia. Positron emission tomography scan in both subjects revealed that MCS influenced regions involved in the circuitry of pain. Copyright (C) 2011 S. Karger AG, Basel

Giant multilocular thymic cyst in an HIV-infected adolescent

A girl with vertically acquired HIV infection presented with a 6-month history of dyspnea and chest pain. Computed tomography of the thorax showed a heterogenous mass measuring 13 x 9 x 17 cm located in the anterior mediastinum. Complete surgical resection was accomplished with no complications. The final diagnosis was multilocular thymic cyst, a distinct pathologic entity that is morphologically distinguishable and unrelated to congenital thymic cyst. (C) 2011 Elsevier Inc. All rights reserved.

Total Pancreatectomy: Porcine Model for Inducing Diabetes - Anatomical Assessment and Surgical Aspects

Background: The swine is an essential model for carrying out preclinical research and for teaching complex surgical procedures. There is a lack of experimental models describing anatomical and surgical aspects of total pancreatectomy in the pig. Materials and Methods: The experiments were performed on 10 white male swine weighing 27-33 kg. The animals were premedicated with midazolam (0.4 mg/kg, i.m.) and ketamine (4 mg/kg, i.m.). Anesthesia was induced with propofol (1-2 mg/kg, i.v.) and was maintained with propofol and fentanyl (0.3 mg and 0.1 mu g/kg/min, respectively, i.v.). The surgical period ranged from 44 to 77 min. The pancreas anatomy, and the main arterial, venous and pancreatic duct anatomy were assessed. Results: The pancreas anatomy was composed of 3 lobes, the `splenic`, `duodenal` and `connecting` lobe which is attached to the anterior portion of the portal vein. The splenic artery and the junction of the splenic vein and portal vein were divided. The left gastric artery was dissected and separated from its origin at the splenic artery. The head of the pancreas is disposed in a C shape. The pancreas was dissected and liberated from the right portion of the portal vein and the infrahepatic vena cava. The pancreas was separated from the duodenum preserving the pancreaticoduodenal artery, then we performed the total pancreatectomy preserving the duodenum, common bile duct and spleen. Conclusion: Total pancreatectomy with duodenum, bile duct and spleen preservation in the pig is feasible and an important instrument for research purposes and teaching surgical technique. Copyright (C) 2010 S. Karger AG, Basel

Reduced medial prefrontal N-Acetyl-Aspartate levels in pediatric major depressive disorder: A multi-voxel in vivo (1)H spectroscopy study

There is increasing evidence of a reciprocal fronto-limbic network in the pathogenesis of mood disorders. Prior in vivo proton ((1)H) spectroscopy studies provide evidence of abnormal neurochemical levels in the cingulate and dorsolateral prefrontal cortex (DLPFC) of adult subjects with major depressive disorder (MOD). We examined whether similar abnormalities occur in children and adolescents with MDD. We collected two-dimensional multi-voxel in vivo 1H spectroscopy data at 1.5 Tesla to quantify levels of N-acetyl-aspartate (NAA), glycerolphosphocholine plus phosphocholine (GPC + PC), and phosphocreatine plus creatine (PCr + Cr) in the DLPFC, medial prefrontal cortex (MPFC), and anterior cingulate (AC) of children and adolescents aged 8-17 years with MDD (n = 16) compared with healthy control subjects (n = 38). Analysis of covariance with age and gender as covariates was performed. MDD subjects showed significantly lower levels of NAA in the right MPFC and right AC than controls. MDD subjects also had significantly lower levels of GPC + PC in the right AC than control subjects. There were no significant differences in other metabolites in the studied regions. Pediatric patients with MDD exhibit neurochemical alterations in prefrontal cortex regions that are important in the monitoring and regulation of emotional states. (C) 2010 Elsevier Ireland Ltd. All rights reserved.