Tatiana Helena Rech

Management of the Brain-Dead Organ Donor: A Systematic Review and Meta-Analysis

Background The shortage of organs is a limitation for transplantation, making the care of potential organ donors an important issue. The present systematic review and meta-analysis was carried out to assess the efficacy of interventions to stabilize hemodynamics in brain-dead donors or to improve organ function and outcomes of transplantation. Methods Medline, Embase, and Cochrane databases were searched. Of 5096 articles retrieved, 39 randomized controlled trials were selected. Twenty were included in a qualitative synthesis, providing data on 1277 patients. The main interventions described were desmopressin use, triiodothyronine and methylprednisolone replacement, fluid management, vasopressor therapy, mechanical ventilation strategies, and surgical techniques. Results Three meta-analyses were conducted: the first included two studies and showed that desmopressin administered to brain-dead patients was not advantageous with respect to early organ function in kidney recipients (relative risk, 0.97; 95% confidence interval [CI], 0.85–1.10; I2=0%; P=0.809). The second included four studies and showed that triiodothyronine did not add hemodynamic benefits versus standard management (weighted mean difference, 0.15; 95% CI, −0.13 to 0.42; I2=17.4%; P=0.304). The third meta-analysis (two studies) showed that ischemic liver preconditioning during harvesting procedures did not benefit survival (relative risk, 1.0; 95% CI, 0.93–1.08; I2=0%; P=0.459). Conclusion The present results suggest limited efficacy of interventions focusing on the management of brain-dead donors.

Neuron-enriched RNA-binding proteins regulate pancreatic beta cell function and survival

Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain, and other human tissues, and we identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1, and Rbfox2, were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, whereas silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.

Pancreatic size and fat content in diabetes: A systematic review and meta-analysis of imaging studies

Objectives Imaging studies are expected to produce reliable information regarding the size and fat content of the pancreas. However, the available studies have produced inconclusive results. The aim of this study was to perform a systematic review and meta-analysis of imaging studies assessing pancreas size and fat content in patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). Methods Medline and Embase databases were performed. Studies evaluating pancreatic size (diameter, area or volume) and/or fat content by ultrasound, computed tomography, or magnetic resonance imaging in patients with T1DM and/or T2DM as compared to healthy controls were selected. Seventeen studies including 3,403 subjects (284 T1DM patients, 1,139 T2DM patients, and 1,980 control subjects) were selected for meta-analyses. Pancreas diameter, area, volume, density, and fat percentage were evaluated. Results Pancreatic volume was reduced in T1DM and T2DM vs. controls (T1DM vs. controls: -38.72 cm3, 95%CI: -52.25 to -25.19, I2 = 70.2%, p for heterogeneity = 0.018; and T2DM vs. controls: -12.18 cm3, 95%CI: -19.1 to -5.25, I2 = 79.3%, p for heterogeneity = 0.001). Fat content was higher in T2DM vs. controls (+2.73%, 95%CI 0.55 to 4.91, I2 = 82.0%, p for heterogeneity<0.001). Conclusions Individuals with T1DM and T2DM have reduced pancreas size in comparison with control subjects. Patients with T2DM have increased pancreatic fat content.

UCP2 expression is increased in pancreas from brain-dead donors and involved in cytokine-induced b cells apoptosis

Background Systemic inflammation associated with brain death (BD) decreases islet yield and quality, negatively affecting outcomes of human islet transplantation. A recent study from our group showed an increased expression of uncoupling protein-2 (UCP2) in pancreas from rats with BD as compared with controls. UCP2 is located in the mitochondrial inner membrane and regulates production of reactive oxygen species and glucose-stimulated insulin secretion. It has been suggested that UCP2 also plays a role in &bgr; cell apoptosis, but these findings remain controversial. Methods We have presently performed a case-control study to assess UCP2 expression in pancreas from BD donors (cases) and subjects who underwent pancreatectomy (controls). We next investigated the role of Ucp2 in cytokine-induced apoptosis of rat insulin-producing INS-1E cells. Results UCP2 gene expression was higher in pancreas from BD donors compared with controls (1.73 ± 0.93 vs 0.75 ± 0.66; fold change, P < 0.05). Ucp2 knockdown (80% at the protein and messenger RNA levels) reduced by 30% cytokine-induced apoptosis and nitric oxide production in INS-1E cells. This protection was associated with decreased expression of cleaved (activated) caspases 9 and 3, suggesting that Ucp2 knockdown interferes with cytokine triggering of the intrinsic apoptotic pathway. Moreover, both messenger RNA and protein concentrations of the antiapoptotic protein Bcl-2 were increased after Ucp2 knockdown in INS-1E cells. Conclusions These data suggest that UCP2 has an apoptotic effect in &bgr; cells via regulation of the intrinsic pathway of apoptosis.

Diabetes insipidus como manifestação inicial de leucemia mieloide aguda em paciente com monossomia do cromossomo 7

O diabetes insipidus (DI) central e uma sindrome caracterizada pela incapacidade de concentracao urinaria devido a deficiencia do hormonio antidiuretico. O envolvimento do sistema nervoso central e frequente nas leucemias, mas a ocorrencia de DI e rara e confere pior prognostico. A patogenese do DI na leucemia nao e totalmente conhecida, mas a infiltracao do eixo hipotalamo-hipofisario por celulas leucemicas parece ser um fator responsavel. O presente relato descreve o caso de um paciente que apresentou DI como primeira manifestacao de leucemia mieloide aguda e que evoluiu com dificuldades de ajustes do sodio serico, da poliuria e da reposicao volemica, necessitando de permanencia prolongada em unidade de cuidados intensivos. Palavras-chave: diabetes insipidus ; leucemia mieloide aguda; monossomia; cromossomo 7.