Depression, Cytokine, and Cytokine by Treatment Interactions Modulate Gene Expression in Antipsychotic Naïve First Episode Psychosis.

In schizophrenia, genetic and environmental factors affect neurodevelopment and neuroprogressive trajectory. Altered expression of neuro-immune genes and increased levels of cytokines are observed, especially in patients with comorbid depression. However, it remains unclear whether circulating levels of cytokines and expression of these genes are associated, and how antipsychotic treatments impact this association. Relationships between messenger RNA (mRNA) expression of 11 schizophrenia-related genes and circulating levels of cytokines (interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α) were analyzed in 174 antipsychotic naïve first episode psychosis (FEP) and in 77 healthy controls. A subgroup of 72 patients was reassessed after treatment with risperidone. FEP patients were divided into those with and without depression. FEP patients with depression showed increased COMT expression and decreased NDEL1 expression. Increased IL-6 was associated with lowered AKT1 and DROSHA expression, while increased IL-10 was associated with increased NDEL1, DISC1, and MBP expression. IL-6 levels significantly increased the risperidone-induced expression of AKT1, DICER1, DROSHA, and COMT mRNA. The differential mRNA gene expression in FEP is largely associated with increased cytokine levels. While increased IL-6 may downregulate AKT-mediated cellular functions and dysregulate genes involved in microRNA (miRNA) machinery, increased IL-10 has neuroprotective properties. Increased IL-6 levels may prime the expression of genes (AKT1, DICER1, DROSHA, and COMT) in response to risperidone, suggesting that cytokine × treatment × gene interactions may improve cell function profiles. FEP patients with depression show a different gene expression profile reinforcing the theory that depression in FEP is a different phenotype.

Increased expression of NDEL1 and MBP genes in the peripheral blood of antipsychotic-naïve patients with first-episode psychosis.

Schizophrenia is a multifactorial neurodevelopmental disorder with high heritability. First-episode psychosis (FEP) is a critical period for determining the disease prognosis and is especially helpful for identifying potential biomarkers associated with the onset and progression of the disorder. We investigated the mRNA expression of 12 schizophrenia-related genes in the blood of antipsychotic-naïve FEP patients (N=73) and healthy controls (N=73). To evaluate the influences of antipsychotic treatment and progression of the disorder, we compared the gene expression within patients before and after two months of treatment with risperidone (N=64). We observed a significantly increased myelin basic protein (MBP) and nuclear distribution protein nudE-like 1 (NDEL1) mRNA levels in FEP patients compared with controls. Comparing FEP before and after risperidone treatment, no significant differences were identified; however; a trend of relatively low NDEL1 expression was observed after risperidone treatment. Animals chronically treated with saline or risperidone exhibited no significant change in Ndel1 expression levels in the blood or the prefrontal cortex (PFC), suggesting that the trend of low NDEL1 expression observed in FEP patients after treatment is likely due to factors other than risperidone treatment (i.e., disease progression). In addition to the recognized association with schizophrenia, MBP and NDEL1 gene products also play an essential role in the functions that are deregulated in schizophrenia, such as neurodevelopment. Our data strengthen the importance of these biological processes in psychotic disorders, indicating that these changes can be detected peripherally and potentially represent putative novel blood biomarkers of susceptibility and disorder progression.

Changes in gene expression and methylation in the blood of patients with first-episode psychosis.

Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was observed in FEP patients relative to controls. Also, when we compare the FEP patients after risperidone treatment with controls, this difference remains significant, and no significant differences were observed in GCH1 mRNA levels when comparing patients before and after risperidone treatment. Additionally, although the differences were non-significant after Bonferroni correction, the expression of GCH1 seemed to be correlated with PANSS scores, and the GCH1 promoter region was more methylated in FEP than in controls, thus corroborating the results obtained at the mRNA level. Few studies have been conducted on GCH1, and future studies are needed to clarify its potential role in the progression of schizophrenia.

Análise da rejeição do transplante de aponeurose em coelhos / Analysis of transplant rejection in rabbits aponeurosis

OBJETIVO: Estudar a viabilidade de aponeurose heteróloga para fechar parede abdominal de coelhos, com ênfase no processo de rejeição. MÉTODOS: Este projeto foi aprovado pelo Comitê de Cuidados Animais da Faculdade de Ciências Médicas da Santa Casa de São Paulo e realizado na Unidade Técnica e Cirurgia Experimental. Quatro coelhas vermelhas trocaram aponeurose da parede abdominal com outros quatro animais machos brancos. Em dois coelhos, foi retirada e substituída a aponeurose como controle do processo cicatricial. Eles foram avaliados 1 vez por dia e sacrificados após 7 dias. Foi realizada a imunoistoquímica com CD20 e CD79. RESULTADOS: Os animais não tiveram celulite, abscesso, hematoma, deiscência da ferida ou hérnia. O local do enxerto mostrou hiperemia intensa. A análise histológica mostrou um processo inflamatório, com a presença de miofibroblastos em amadurecimento e colágeno, que variou de incipiente a moderado. O número de vasos estava reduzido e as células inflamatórias foram, em sua maioria, células plasmáticas e macrófagos. Não havia sinais morfológicos da rejeição aguda com a agressão do endotélio vascular. O músculo adjacente mostrou sinais de degeneração, com reação inflamatória dos núcleos e condensação do citoplasma. A análise imunoistoquímica (CD20 e CD79) mostrou que o processo inflamatório não foi mediado por linfócitos. O teste não paramétrico de Mann-Whitney mostrou que não se pode rejeitar a hipótese de igualdade (p>0,05). CONCLUSÃO: Não houve complicações pós-operatórias (fístulas, deiscência etc.) e a análise histológica revelou processo inflamatório inespecífico. A análise imunoistoquímica mostrou que o processo inflamatório não foi em razão de uma possível rejeição.

OBJECTIVE: To study the feasibility of heterologous aponeurosis to close the abdominal wall of rabbits emphasizing the rejection process. METHODS: This project was approved by the Animals Care Committee of the Faculdade de Ciências Médicas da Santa Casa de São Paulo, and it was carried out at the Experimental Surgery and Technical Unit. Four red female rabbits exchanged abdominal wall aponeurosis with other four white male animals. Two rabbits just had it removed and replaced to be the control group for the healing process. Animals were evaluated once a day, and after 7 days they were sacrificed. Immunohistochemical analysis with CD20 and CD79 was done. RESULTS: The animals did not have cellulitis, abscess, hematoma, wound dehiscence or herniation. The graft site showed intense hyperemia. The histological analysis showed an inflammatory process with maturing myofibroblasts and collagen ranging from incipient to moderate. The number of vessels was reduced and the inflammatory cells were most plasma cells and macrophages. There were no morphological signs of acute rejection with aggressive vascular endothelial damage. The adjacent muscle showed signs of degeneration with inflammatory centralization of nuclei and cytoplasmic condensation. The immunohistochemical analysis (CD20 and CD79) showed that the inflammatory process was not mediated by lymphocytes. Mann-Whitney nonparametric test showed that the hypothesis of equality (p>0.05) should not be discarded. CONCLUSION: There were no postoperative complications (fistulas, dehiscence etc.) and the histological analysis showed nonspecific inflammatory process. The immunohistochemical analysis showed that the inflammatory process was not due to a possible rejection.

Analysis of transplant rejection in rabbits aponeurosis.

OBJECTIVE: To study the feasibility of heterologous aponeurosis to close the abdominal wall of rabbits emphasizing the rejection process. METHODS: This project was approved by the Animals Care Committee of the Faculdade de Ciências Médicas da Santa Casa de São Paulo, and it was carried out at the Experimental Surgery and Technical Unit. Four red female rabbits exchanged abdominal wall aponeurosis with other four white male animals. Two rabbits just had it removed and replaced to be the control group for the healing process. Animals were evaluated once a day, and after 7 days they were sacrificed. Immunohistochemical analysis with CD20 and CD79 was done. RESULTS: The animals did not have cellulitis, abscess, hematoma, wound dehiscence or herniation. The graft site showed intense hyperemia. The histological analysis showed an inflammatory process with maturing myofibroblasts and collagen ranging from incipient to moderate. The number of vessels was reduced and the inflammatory cells were most plasma cells and macrophages. There were no morphological signs of acute rejection with aggressive vascular endothelial damage. The adjacent muscle showed signs of degeneration with inflammatory centralization of nuclei and cytoplasmic condensation. The immunohistochemical analysis (CD20 and CD79) showed that the inflammatory process was not mediated by lymphocytes. Mann-Whitney nonparametric test showed that the hypothesis of equality (p>0.05) should not be discarded. CONCLUSION: There were no postoperative complications (fistulas, dehiscence etc.) and the histological analysis showed nonspecific inflammatory process. The immunohistochemical analysis showed that the inflammatory process was not due to a possible rejection.

[Intestinal lengthening using a gastric graft: experimental study in pigs]. / Alongamento de intestino com tubo gástrico: estudo piloto em porcos.

OBJECTIVE: Novel experimental technique of intestinal lengthening with a gastric graft in swines is proposed. METHODS: Four male large white swines, weighing 15 to 20 kg and aging 50 to 60 days were underwent an intestinal lengthening using a gastric graft (Figure 1). Swines were re-operated to check the aspect of the lengthening surgery. At this time intestinal fragments of suture lines, respecting a 5 cm margin, were removed and sent to histological analysis. RESULTS: There wasn't any graft ischemia or necrosis, residual stomach was already dilated by the time of relaparotomies, regaining 50% of its original size. Only an intense atrophy of the gastric graft mucosa with no signs of necrosis at histological study (Figure 2). CONCLUSION: Lengthening using a gastric graft is technically feasible, with viability of the graft. Studies with swines with SBS in a larger cohort will be necessary to analyze stomach graft function. In the future, this technique can be a bridge to intestinal transplantation.

Alongamento de intestino com tubo gástrico: estudo piloto em porcos / Intestinal lengthening using a gastric graft: experimental study in pigs

OBJETIVO: Apresentar uma nova técnica de alongamento intestinal usando enxerto gástrico em suínos. MÉTODOS: Quatro porcos machos large white pesando de 15 a 20 kg. foram submetidos ao alongamento intestinal utilizando enxerto gástrico. Os porcos foram reoperados para observação do aspecto da operação, neste momento, fragmentos intestinais contendo as linhas de sutura, respeitando uma margem de 5 cm, foram removidos e enviados para análise histológica. RESULTADOS: O estômago residual estava dilatado no momento da necrópsia, recuperando aproximadamente 50 por cento do seu tamanho original aproximadamente 15 dias após a operação de alongamento. Somente atrofia intensa da mucosa gástrica foi observada no estudo histológico de todas as amostras, sem sinais de necrose. CONCLUSÃO: O alongamento com enxerto gástrico é tecnicamente viável, comprovado pela viabilidade do enxerto. Estudos com suínos com o SIC em uma maior cohort, serão necessários para analisar a função do enxerto gástrico. No futuro, essa técnica pode ser uma ponte para o transplante intestinal.

OBJECTIVE: Novel experimental technique of intestinal lengthening with a gastric graft in swines is proposed. METHODS: Four male large white swines, weighing 15 to 20 kg and aging 50 to 60 days were underwent an intestinal lengthening using a gastric graft (Figure 1). Swines were re-operated to check the aspect of the lengthening surgery. At this time intestinal fragments of suture lines, respecting a 5 cm margin, were removed and sent to histological analysis. RESULTS: There wasn't any graft ischemia or necrosis, residual stomach was already dilated by the time of relaparotomies, regaining 50 percent of its original size. Only an intense atrophy of the gastric graft mucosa with no signs of necrosis at histological study (Figure 2). CONCLUSION: Lengthening using a gastric graft is technically feasible, with viability of the graft. Studies with swines with SBS in a larger co-hort will be necessary to analyze stomach graft function. In the future, this technique can be a bridge to intestinal transplantation.

Comparative study between parietal peritoneum suture and nonsuture in midline laparotomies in rats / Estudo comparativo entre sutura e não sutura do peritônio parietal nas laparotomias medianas em ratos

PURPOSE: Compare the parietal peritoneum suture and nonsuture in midline laparotomies in rats, as for the formation of adhesions. METHODS: 40 adult albino Wistar rats (20 males and 20 females) underwent a surgery, weighing between 350 and 400 grams. After anesthesia, a midline laparotomy was performed, followed by cavity closure with and without peritoneum suture. After 40 days, the rats underwent a new surgery in order to verify the peritoneum and check if there were any adhesions, and the rats were then sacrificed. RESULTS: Statistical analysis showed there was no significant difference between the adhesions occurring or not with peritoneal suture or nonsuture, including in relation to the rats' gender. CONCLUSION: Closing the peritoneum or not does not interfere with the formation of adhesions after midline laparotomies in rats from both genders.

OBJETIVO: Comparar a sutura e não sutura do peritônio parietal nas laparotomias medianas em ratos, quanto à formação de aderências. MÉTODOS: Foram operados 40 ratos albinos Wistar (20 machos e 20 fêmeas), adultos, pesando entre 350 e 400 gramas. Após a anestesia, foi realizada laparotomia mediana seguida de fechamento da cavidade com sutura do peritônio e sem sutura do peritônio. Após 40 dias, os animais foram re-operados para a inspeção do peritônio e a constatação da presença ou não de aderências e, em seguida, sacrificados. RESULTADOS: A análise estatística demonstrou que não houve diferença significativa entre a ocorrência ou não de aderências com sutura e não sutura do peritônio, nem com relação ao sexo dos animais operados. CONCLUSÃO: O fechamento ou não do peritônio não interfere na formação de aderências após laparotomias medianas em ratos de ambos os sexos.

Comparative study between parietal peritoneum suture and nonsuture in midline laparotomies in rats.

PURPOSE: Compare the parietal peritoneum suture and nonsuture in midline laparotomies in rats, as for the formation of adhesions. METHODS: 40 adult albino Wistar rats (20 males and 20 females) underwent a surgery, weighing between 350 and 400 grams. After anesthesia, a midline laparotomy was performed, followed by cavity closure with and without peritoneum suture. After 40 days, the rats underwent a new surgery in order to verify the peritoneum and check if there were any adhesions, and the rats were then sacrificed. RESULTS: Statistical analysis showed there was no significant difference between the adhesions occurring or not with peritoneal suture or nonsuture, including in relation to the rats' gender. CONCLUSION: Closing the peritoneum or not does not interfere with the formation of adhesions after midline laparotomies in rats from both genders.