Paulo Clemente Sallet

Brazilian Multicenter Study of the Intragastric Balloon

Background: Intragastric balloons have been used in obese patients to provide early satiety and thereby induce weight loss. Several studies have reported promising results with a new balloon (BIB®) designed to overcome some of the technical pitfalls of earlier devices. We assessed both safety and effectiveness of the BIB®. Method: From November 2000 to February 2004, 483 overweight and obese patients were treated with the BIB®. 323 patients completed a 6-month follow-up, and 85 of them completed a 1-year follow-up. All patients took part in a multidisciplinary program involving clinical, psychiatric, physical training, and dietary approaches. Results: Compared to baseline values, after a 6-month follow-up subjects showed significant reductions in weight (15.2 ± 10.5 kg), percent excess weight loss (48.3 ± 28.1), and BMI (-5.3 ± 3.4 kg/m2) (P < 0.000). At 1-year follow-up, 85 patients have maintained more than 90% of their BMI reduction. The main side-effects were nausea/vomiting (40%), and epigastric pain (20%), requiring removal of the BIB ® in 11 patients (3.4%). Minor complications were reflux esophagitis (12%) and symptomatic gastric stasis (9%). Balloon impaction occurred in 2 cases (0.6%), and in 1 patient (0.3%) there was spontaneous deflation of the balloon leading to a small-bowel obstruction solved by a surgical approach. Conclusion: The BIB® has been effective to temporarily control obesity, inducing an excess weight loss of approximately 48%. It was not associated with mortality and showed minimal risk of major complications.

Polymorphisms in genes involved in neurodevelopment may be associated with altered brain morphology in schizophrenia: Preliminary evidence

An abnormality in neurodevelopment is one of the most robust etiologic hypotheses in schizophrenia (SZ). There is also strong evidence that genetic factors may influence abnormal neurodevelopment in the disease. The present study evaluated in SZ patients, whose brain structural data had been obtained with magnetic resonance imaging (MRI), the possible association between structural brain measures, and 32 DNA polymorphisms, located in 30 genes related to neurogenesis and brain development. DNA was extracted from peripheral blood cells of 25 patients with schizophrenia, genotyping was performed using diverse procedures, and putative associations were evaluated by standard statistical methods (using the software Statistical Package for Social Sciences - SPSS) with a modified Bonferroni adjustment. For reelin (RELN), a protease that guides neurons in the developing brain and underlies neurotransmission and synaptic plasticity in adults, an association was found for a non-synonymous polymorphism (Val997Leu) with left and right ventricular enlargement. A putative association was also found between protocadherin 12 (PCDH12), a cell adhesion molecule involved in axonal guidance and synaptic specificity, and cortical folding (asymmetry coefficient of gyrification index). Although our results are preliminary, due to the small number of individuals analyzed, such an approach could reveal new candidate genes implicated in anomalous neurodevelopment in schizophrenia.

Rightward cerebral asymmetry in subtypes of schizophrenia according to Leonhard's classification and to DSM-IV: a structural MRI study

Although well documented, brain structural abnormalities in schizophrenia are non-specific, and morphometric parameters show significant overlap between patients and healthy controls. Such inconsistencies in neuroimaging findings could represent different levels of severity along a single pathogenic process or distinct clinical and etiopathological psychoses within a schizophrenic spectrum. The aim of the present study was the investigation of distinct brain abnormalities in different subtypes of schizophrenia. Forty patients were classified according to DSM-IV and Leonhards classifications. Psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS) and the Negative Symptom Rating Scale (NSRS). Patients were compared to 20 healthy volunteers on volumetric measures of cerebral structures (hemisphere, hippocampus and planum temporale) and ventricular-brain ratio (VBR) obtained by magnetic resonance imaging. Patients showed rightward asymmetry of cerebral hemispheres and increased VBR. Rightward asymmetry correlated with severity of negative symptoms and prevailed in the systematic forms of Leonhard, suggesting a distinct pattern of left hemisphere abnormality in this subgroup of psychoses. Increased VBR values showed a single normal distribution in the subgroups, indicating that ventricular enlargement is not restricted to a subgroup but is present to a certain degree in all cases.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness

Background: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. Methods: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes. Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. Conclusion: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Nogo CAA 3'UTR insertion polymorphism is not associated with schizophrenia nor with bipolar disorder

The Nogo gene maps to 2p14-p13, a region consistently associated with schizophrenia and bipolar disorder. The association of a polymorphism in Nogo was previously investigated by two groups, with divergent results. In this report, using an alternative approach, we evaluated this same polymorphism in 725 individuals, including patients with schizophrenia, bipolar disorder, normal controls and non-human primate samples. Our results indicate that the polymorphism is not associated with any of these diseases, but has a remarkably biased distribution in ethnic groups. Genotyping of primate samples, suggest that this polymorphism is a recent event in human speciation.

Exploring the knowledge contained in neuroimages: Statistical discriminant analysis and automatic segmentation of the most significant changes

OBJECTIVE The aim of this article is to propose an integrated framework for extracting and describing patterns of disorders from medical images using a combination of linear discriminant analysis and active contour models. METHODS A multivariate statistical methodology was first used to identify the most discriminating hyperplane separating two groups of images (from healthy controls and patients with schizophrenia) contained in the input data. After this, the present work makes explicit the differences found by the multivariate statistical method by subtracting the discriminant models of controls and patients, weighted by the pooled variance between the two groups. A variational level-set technique was used to segment clusters of these differences. We obtain a label of each anatomical change using the Talairach atlas. RESULTS In this work all the data was analysed simultaneously rather than assuming a priori regions of interest. As a consequence of this, by using active contour models, we were able to obtain regions of interest that were emergent from the data. The results were evaluated using, as gold standard, well-known facts about the neuroanatomical changes related to schizophrenia. Most of the items in the gold standard was covered in our result set. CONCLUSIONS We argue that such investigation provides a suitable framework for characterising the high complexity of magnetic resonance images in schizophrenia as the results obtained indicate a high sensitivity rate with respect to the gold standard.

State-dependent microstructural white matter changes in drug-naive patients with first-episode psychosis

BACKGROUND Diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) microstructural abnormalities in schizophrenia. Whether or not such alterations could vary depending on clinical status (i.e. acute psychosis v. remission) remains to be investigated. METHODS Twenty-five treatment-naïve first-episode psychosis (FEP) patients and 51 healthy-controls (HC) underwent MRI scanning at baseline. Twenty-one patients were re-scanned as soon as they achieved sustained remission of symptoms; 36 HC were also scanned twice. Rate-of-change maps of longitudinal DTI changes were calculated for in order to examine WM alterations associated with changes in clinical status. We conducted voxelwise analyses of fractional anisotropy (FA) and trace (TR) maps. RESULTS At baseline, FEP presented reductions of FA in comparison with HC [p < 0.05, false-discovery rate (FDR)-corrected] affecting fronto-limbic WM and associative, projective and commissural fasciculi. After symptom remission, patients showed FA increase over time (p < 0.001, uncorrected) in some of the above WM tracts, namely the right anterior thalamic radiation, right uncinate fasciculus/inferior fronto-occipital fasciculus, and left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. We also found significant correlations between reductions in PANSS scores and FA increases over time (p < 0.05, FDR-corrected). CONCLUSIONS WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities in brain tracts are a key neurobiological feature of acute psychotic disorders, and recovery from such WM pathology can lead to amelioration of symptoms.

Neuropeptide Downregulation in Sepsis

Neuropeptides are an extremely conserved arm of neurobiology. Despite their effects as neurohormones and neurotransmitters, a multitude of other effects have been described, putting in evidence their importance as regulators of immune responses, such as chemotaxis, oxidative burst, pro-inflammatory signaling, and many others. The effects of neuropeptides in the pathophysiology of sepsis, however, remain poorly investigated. A prospective cohort study to investigate the effects of neuropeptides in sepsis was carried out. Here, we describe that neuropeptides are downregulated during septic shock. We propose that it may be a protective mechanism of the host to avoid further inflammatory injury.

Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis

Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naïve first-episode psychosis patients (n=43) at baseline and following symptom remission, and in healthy controls (n=77). At baseline GSK3B total level was higher in patients (p<0.001). In schizophrenia spectrum patients (n=25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n=18) (p<0.001; p=0.027; p=0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular.

Nobel Prize: dynamite, neurosciences and other ironies

Endereco para correspondencia: Paulo Clemente Sallet. Instituto de Psiquiatria – HCFMUSP. Rua Ovidio Pires de Campos, 785 – 05403-903 – Sao Paulo, SP. E-mail: pcsallet@usp.br Criada em 1895 pelo cientista sueco Alfred Nobel, a Fundacao Nobel passou a premiar personalidades internacionais com destaque no âmbito da Fisica, da Quimica, da Medicina, da Literatura e da promocao da paz a partir de 1901. Nobel, embora celebrado como cientista, empreendedor e pacifista, como todos sabem, tem no seu curriculo o merito de ter inventado a dinamite. Nada tao escandaloso quanto Mikhail Kalashnikov ser cogitado para o Nobel da Paz, mas ainda assim uma ironia. E as ironias nao param aqui. Ja na primeira edicao do Premio Nobel, em 1901, Golgi fora cogitado para receber o premio em Fisiologia ou Medicina pelo comite de professores do Instituto Karolinska (Estocolmo). Camillo Golgi (1843-1926), nascido em Corteno (montanhas proximas a Brescia, norte da Italia), estudou Medicina na Universidade de Pavia, cujo Instituto de Psiquiatria na epoca era dirigido por Cesare Lombroso (1835-1909). Golgi tambem trabalhou no laboratorio de patologia de Giulio Bizzozero (1846-1901), professor de Histologia e Patologia, ao qual, entre outros aportes, atribui-se o descobrimento das propriedades hematopoieticas da medula ossea. Entretanto, foi somente em 1906 que Golgi recebeu o Nobel, pela primeira vez na historia da premiacao compartilhado com outro cientista, o espanhol Santiago Ramon y Cajal (1852-1934) (Figura 1). Cajal nasceu em Petilla de Aragon, teria preferido seguir a carreira artistica, mas por influencia de seu pai (professor de Anatomia) formou-se em Medicina na Universidade de Saragoza. Em 1887, foi nomeado professor de Histologia e Anatomia em Barcelona e, em seguida, ocupou a mesma cadeira em Madri (1892). Os conhecimentos atuais sobre estrutura e funcao neuronais, em grande parte, baseiam-se nos principios da localizacao funcional e na chamada doutrina do neuronio, ambos estabelecidos a partir do seculo XIX. Por localizacao funcional entende-se que diferentes partes Figura 1. Fotografias de Camillo Golgi (1843-1926), a esquerda, e de Santiago Ramon y Cajal (1852-1934), a direita, obtidas no site da Fundacao Premio Nobel (http://nobelprize.org/nobel_prizes/medicine/laureates/1906/).