Schizophrenia, brain disease and meta-analyses: Integrating the pieces and testing Fusar-Poli`s hypothesis

This paper aims to discuss and test the hypothesis raised by Fusar-Poli [Fusar-Poli P. Can neuroimaging prove that schizophrenia is a brain disease? A radical hypothesis. Medical Hypotheses in press, corrected proof] that ""on the basis of the available imaging literature there is no consistent evidence to reject the radical and provocative hypothesis that schizophrenia is not a brain disease"". To achieve this goal, all meta-analyses on `fMRI and schizophrenia` published during the current decade and indexed in Pubmed were summarized, as much as some other useful information, e.g., meta-analyses on genetic risk factors. Our main conclusion is that the literature fully supports the hypothesis that schizophrenia is a syndrome (not a disease) associated with brain abnormalities, despite the fact that there is no singular and reductionist pathway from the nosographic entity (schizophrenia) to its causes. This irreducibility is due to the fact that the syndrome has more than one dimension (e.g., cognitive, psychotic and negative) and each of them is related to abnormalities in specific neuronal networks. A psychiatric diagnosis is a statistical procedure; these dimensions are not identically represented in each diagnosticated case and this explains the existence of more than one pattern of brain abnormalities related to schizophrenia. For example, chronification is associated with negativism while the first psychotic episode is not; in that sense, the same person living with schizophrenia may reveal different symptoms and fMRI patterns along the course of his life, and this is precisely what defines schizophrenia since the time when it was called Dementia Praecox (first by pick then by Kraepelin). It is notable that 100% of the collected meta-analyses on `fMRI and schizophrenia` reveal positive findings. Moreover, all meta-analyses that found positive associations between schizophrenia and genetic risk factors have to do with genes (SNPs) especially activated in neuronal tissue of the central nervous system (CNS), suggesting that, to the extent these polymorphisms are related to schizophrenia`s etiology, they are also related to abnormal brain activity. (C) 2009 Elsevier Ltd. All rights reserved.

Evaluation of bacterial infections in organ transplantation

Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo

GREB1 tissue expression is associated with organ-confined prostate cancer

Objective: By reason of its heterogeneous behavior, it is difficult to determine the prognosis of many prostate cancer cases. Patients with the same clinicopathologic conditions may present varying clinical findings and rates of progression. We determined the role of new genes as potential molecular markers for prostate cancer prognosis. Materials and methods: We performed a microarray analysis of two pools of patients with prostate cancer divided according to their clinicopathologic characteristics. After that, we validated these results by testing the genes with most different expressions between the two pools using the quantitative real time polymerase chain reaction method. We analyzed gene expression in 33 patients with localized prostate cancer according to prostate specific antigen (PSA), pathologic stage, Gleason score, and biochemical recurrence. For statistical analysis we used the Mann-Whitney Test. Results: The microarray analysis revealed that 4,147 genes presented a different expression between the two pools. Among them, 3 genes, TMEFF2, GREB1, and THIL,, were at least 13-times overexpressed, and 1 gene, IGH3, which was at least 5times under-expressed in pool 1 (good prognosis) compared with pool 2 (bad prognosis), were selected for analysis. After the validation tests, GREB1 was significantly more overexpressed among patients with stage T2 compared with T3 (P = 0.020). The expressions of other 3 genes did not present significant differences according to the clinicopatholoOcal variables. Conclusions: Tissue expression of GREB1 is associated with organ-confined prostate cancer and may constitute a gene associated with a favorable prognosis. (C) 2012 Elsevier Inc. All rights reserved.

Aerial organ anatomy of Smilax syphilitica (Smilacaceae)

Smilax L. in Brazil is represented by 32 taxa and it is a taxonomically difficult genus because the plants are dioecious and show wide phenotypic variation. The analysis and use of leaf anatomy characters is recognized as a frequently successful taxonomic method to distinguish between individual taxon, when floral material is absent or minute differences in flowers and foliage exist such as in Smilax. The aim of this study was to characterize the anatomical features of the aerial organs in Smilax syphilitica collected from the Atlantic Rainforest, in Santa Teresa-ES and the Smilax aff syphilitica from the Amazon Rainforest, in Manaus, Brazil. For this, a total of three samples of Smilax were collected per site. Sample leaves and stems were fixed with FAA 50, embedded in historesin, sectioned on a rotary microtome, stained and mounted in synthetic resin. Additionally, histochemical tests were performed and cuticle ornamentation was analyzed with standard scanning electron microscopy. S. syphilitica and S. aff syphilitica differed in cuticle ornamentation, epidermal cell arrangement and wall thickness, stomata type and orientation, calcium oxalate crystal type, and position of stem thorns. Leaf blades of S. syphilitica from the Amazon Rainforest have a network of rounded ridges on both sides, while in S. aff syphilitica, these ridges are parallel and the spaces between them are filled with numerous membranous platelets. Viewed from the front, the epidermal cells of S. syphilitica have sinuous walls (even more pronounced in samples from the Amazon); while in S. aff syphilitica, these cells are also sinuous but elongated in the cross-section of the blade and arranged in parallel. Stomata of S. syphilitica are paracytic, whereas in S. aff syphilitica, are both paracytic and anisocytic, and their polar axes are directed towards the mid-vein. Calcium oxalate crystals in S. syphilitica are prisms, whereas in S. aff syphilitica, crystal sand. Thorns occur in nodes and internodes in S. syphilitica but only in internodes in S. aff syphilitica. These features have proven to be of diagnostic value and may support a separation into two species, but future studies are needed to confirm that S. aff syphilitica is indeed a new taxon. Rev. Biol. Trop. 60(3): 1137-1148. Epub 2012 September 01.

Influence of brain death and associated trauma on solid organ histological characteristics

PURPOSE: To evaluate histopathological alterations triggered by brain death and associated trauma on different solid organs in rats. METHODS: Male Wistar rats (n=37) were anesthetized with isoflurane, intubated and mechanically ventilated. A trepanation was performed and a balloon catheter inserted into intracraninal cavity and rapidly inflated with saline to induce brain death. After induction, rats were monitored for 30, 180, and 360 min for hemodynamic parameters and exsanguinated from abdominal aorta. Heart, lung, liver, and kidney were removed and fixed in paraffin to evaluation of histological alterations (H&E). Sham-operated rats were trepanned only and used as control group. RESULTS: Brain dead rats showed a hemodynamic instability with hypertensive episode in the first minute after the induction followed by hypotension for approximately 1 h. Histological analyses showed that brain death induces vascular congestion in heart (p<0.05), and lung (p<0.05); lung alveolar edema (p=0.001), kidney tubular edema (p<0.05); and leukocyte infiltration in liver (p<0.05). CONCLUSIONS: Brain death induces hemodynamic instability associated with vascular changes in solid organs and compromises most severely the lungs. However, brain death associated trauma triggers important pathophysiological alterations in these organs.

Regular and moderate exercise before experimental sepsis reduces the risk of lung and distal organ injury

de Araujo CC, Silva JD, Samary CS, Guimaraes IH, Marques PS, Oliveira GP, do Carmo LGRR, Goldenberg RC, Bakker-Abreu I, Diaz BL, Rocha NN, Capelozzi VL, Pelosi P, Rocco PRM. Regular and moderate exercise before experimental sepsis reduces the risk of lung and distal organ injury. J Appl Physiol 112: 1206-1214, 2012. First published January 19, 2012; doi:10.1152/japplphysiol.01061.2011.-Physical activity modulates inflammation and immune response in both normal and pathologic conditions. We investigated whether regular and moderate exercise before the induction of experimental sepsis reduces the risk of lung and distal organ injury and survival. One hundred twenty-four BALB/c mice were randomly assigned to two groups: sedentary (S) and trained (T). Animals in T group ran on a motorized treadmill, at moderate intensity, 5% grade, 30 min/day, 3 times a week for 8 wk. Cardiac adaptation to exercise was evaluated using echocardiography. Systolic volume and left ventricular mass were increased in T compared with S group. Both T and S groups were further randomized either to sepsis induced by cecal ligation and puncture surgery (CLP) or sham operation (control). After 24 h, lung mechanics and histology, the degree of cell apoptosis in lung, heart, kidney, liver, and small intestine villi, and interleukin (IL)-6, KC (IL-8 murine functional homolog), IL-1 beta, IL-10, and number of cells in bronchoalveolar lavage (BALF) and peritoneal lavage (PLF) fluids as well as plasma were measured. In CLP, T compared with S groups showed: 1) improvement in survival; 2) reduced lung static elastance, alveolar collapse, collagen and elastic fiber content, number of neutrophils in BALF, PLF, and plasma, as well as lung and distal organ cell apoptosis; and 3) increased IL-10 in BALF and plasma, with reduced IL-6, KC, and IL-1 beta in PLF. In conclusion, regular and moderate exercise before the induction of sepsis reduced the risk of lung and distal organ damage, thus increasing survival.

Effects of Continuous Erythropoietin Receptor Activator in Sepsis-Induced Acute Kidney Injury and Multi-Organ Dysfunction

Background: Despite advances in supportive care, sepsis-related mortality remains high, especially in patients with acute kidney injury (AKI). Erythropoietin can protect organs against ischemia and sepsis. This effect has been linked to activation of intracellular survival pathways, although the mechanism remains unclear. Continuous erythropoietin receptor activator (CERA) is an erythropoietin with a unique pharmacologic profile and long half-life. We hypothesized that pretreatment with CERA would be renoprotective in the cecal ligation and puncture (CLP) model of sepsis-induced AKI. Methods: Rats were randomized into three groups: control; CLP; and CLP+CERA (5 mu g/kg body weight, i.p. administered 24 h before CLP). At 24 hours after CLP, we measured creatinine clearance, biochemical variables, and hemodynamic parameters. In kidney tissue, we performed immunoblotting-to quantify expression of the Na-K-2Cl cotransporter (NKCC2), aquaporin 2 (AQP2), Toll-like receptor 4 (TLR4), erythropoietin receptor (EpoR), and nuclear factor kappa B (NF-kappa B)-and immunohistochemical staining for CD68 (macrophage infiltration). Plasma interleukin (IL)-2, IL-1 beta, IL-6, IL-10, interferon gamma, and tumor necrosis factor alpha were measured by multiplex detection. Results: Pretreatment with CERA preserved creatinine clearance and tubular function, as well as the expression of NKCC2 and AQP2. In addition, CERA maintained plasma lactate at normal levels, as well as preserving plasma levels of transaminases and lactate dehydrogenase. Renal expression of TLR4 and NF-kappa B was lower in CLP+CERA rats than in CLP rats (p<0.05 and p<0.01, respectively), as were CD68-positive cell counts (p<0.01), whereas renal EpoR expression was higher (p<0.05). Plasma levels of all measured cytokines were lower in CLP+CERA rats than in CLP rats. Conclusion: CERA protects against sepsis-induced AKI. This protective effect is, in part, attributable to suppression of the inflammatory response.

Prevalence of non-organ-specific autoantibodies in a rural community from northeastern Brazil: a population-based study

Non-organ-specific autoantibodies (NOSA) are well-recognized diagnostic markers of autoimmune hepatitis (All-l) and primary biliary cirrhosis (PBC), but can also be observed in patients with viral hepatitis as well as in healthy subjects. The aim of this study was to evaluate the prevalence of NOSA in subjects living in a rural community in Brazil and to correlate their occurrence with the presence of liver disease. Seven hundred twenty-five apparently healthy subjects were randomly selected for assessment of antinuclear (ANA), anti-smooth muscle (SMA), antimitochondrial (AMA), anti-liver/kidney microsome type 1, and anti-liver cytosol type 1 antibodies. Subjects with those NOSA were evaluated for the presence of AIH, PBC, and viral hepatitis. Reactivities for all NOSA, SMA, ANA, and AMA were detected, respectively, in 14, 10, 4, and 0.1% of subjects, with a mean titer of 1:40. NOSA-positive subjects were significantly older and more frequently females. No correlation was observed between the occurrence of NOSA and PBC. AIH, or viral hepatitis. The prevalence of NOSA in Brazilians was 14%. They were usually low titer. NOSA were more frequently observed in females and older subjects and their presence was not correlated with the presence of AIH, PBC, or viral hepatitis. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Organ-specific autoantibodies and autoimmune diseases in juvenile systemic lupus erythematosus and juvenile dermatomyositis patients

Objectives To our knowledge, no study assessed simultaneously a variety of organ-specific autoantibodies and the prevalence of organ-specific autoimmune diseases in juvenile systemic lupus erythematosus (ISLE) and juvenile dermatomyositis (JDM). Therefore, the purpose of this study was to evaluate organ-specific autoantibodies and autoimmune diseases in JSLE and JDM patients. Methods Forty-one JSLE and 41 JDM patients were investigated for autoantibodies associated with autoimmune hepatitis, primary biliary cirrhosis, type I diabetes mellitus (TIDM, autoimmune thyroiditis (AT), autoimmune gastritis and coeliac disease (CD). Patients with positive antibodies were investigated for the respective organ-specific autoimmune diseases. Results Mean age at diagnosis was higher in ISLE compared to JDM patients (10.3 +/- 3.4 vs. 7.3 +/- 3.1 years, p=0.0001). The frequencies of organ-specific autoantibodies were similar in JSLE and JDM patients (p>0.05). Of note, a high prevalence of TIDM and AT autoantibodies was observed in both groups (20% vs. 15%, p=0.77 and 24% vs. 15%, p=0.41; respectively). Higher frequencies of ANA (93% vs. 59%, p=0.0006), anti-dsDNA (61% vs. 2%, p<0.0001), anti-Ro, anti-Sm, anti-RNP, anti-La and IgG-aCL were observed in JSLE (p<0.05). Organ-specific autoimmune diseases were evidenced only in ISLE patients (24% vs. 0%, p=0.13). Two ISLE patients had TIDM associated with Hashimoto thyroiditis and another had subclinical thyroiditis. Another JSLE patient had CD diagnosis based on iron deficiency anaemia, anti-endomysial antibody, duodenal biopsy compatible to CD and response to a gluten-free diet. Conclusions Organ-specific diseases were observed solely in ISLE patients and required specific therapy. The presence of these antibodies recommends the evaluation of organ-specific diseases and a rigorous follow-up.

Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

Abstract Background The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Methods Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. Results The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. Conclusion CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.