Functional and genetic analysis in type 2 diabetes of Liver X receptor alleles – a cohort study

<p>Abstract</p> <p>Background</p> <p>Liver X receptor alpha <it>(LXRA</it>) and beta (<it>LXRB</it>) regulate glucose and lipid homeostasis in model systems but their importance in human physiology is poorly understood. This project aimed to determine whether common genetic variations in <it>LXRA </it>and <it>LXRB </it>associate with type 2 diabetes (T2D) and quantitative measures of glucose homeostasis, and, if so, reveal the underlying mechanisms.</p> <p>Methods</p> <p>Eight common single nucleotide polymorphisms in <it>LXRA </it>and <it>LXRB </it>were analyzed for association with T2D in one French cohort (N = 988 cases and 941 controls), and for association with quantitative measures reflecting glucose homeostasis in two non-diabetic population-based samples comprising N = 697 and N = 1344 adults. Investigated quantitative phenotypes included fasting plasma glucose, serum insulin, and HOMA_IRas measure of overall insulin resistance. An oral glucose tolerance test was performed in N = 1344 of adults. The two alleles of the proximal <it>LXRB </it>promoter, differing only at the SNP rs17373080, were cloned into reporter vectors and transiently transfected, whereupon allele-specific luciferase activity was measured. rs17373080 overlapped, according to <it>in silico </it>analysis, with a binding site for Nuclear factor 1 (NF1). Promoter alleles were tested for interaction with NF1 using direct DNA binding and transactivation assays.</p> <p>Results</p> <p>Genotypes at two <it>LXRB </it>promoter SNPs, rs35463555 and rs17373080, associated nominally with T2D (P values 0.047 and 0.026). No <it>LXRA </it>or <it>LXRB </it>SNP associated with quantitative measures reflecting glucose homeostasis. The rs17373080 C allele displayed higher basal transcription activity (P value < 0.05). The DNA-mobility shift assay indicated that oligonucleotides corresponding to either rs17373080 allele bound NF1 transcription factors in whole cell extracts to the same extent. Different NF1 family members showed different capacity to transactivate the <it>LXRB </it>gene promoter, but there was no difference between promoter alleles in NF1 induced transactivation activity.</p> <p>Conclusion</p> <p>Variations in the <it>LXRB </it>gene promoter may be part of the aetiology of T2D. However, the association between <it>LXRB </it>rs35463555 and rs17373080, and T2D are preliminary and needs to be investigated in additional larger cohorts. Common genetic variation in <it>LXRA </it>is unlikely to affect the risk of developing T2D or quantitative phenotypes related to glucose homeostasis.</p

Study of FoxA Pioneer Factor at Silent Genes Reveals Rfx-Repressed Enhancer at Cdx2 and a Potential Indicator of Esophageal Adenocarcinoma Development

Understanding how silent genes can be competent for activation provides insight into development as well as cellular reprogramming and pathogenesis. We performed genomic location analysis of the pioneer transcription factor FoxA in the adult mouse liver and found that about one-third of the FoxA bound sites are near silent genes, including genes without detectable RNA polymerase II. Virtually all of the FoxA-bound silent sites are within conserved sequences, suggesting possible function. Such sites are enriched in motifs for transcriptional repressors, including for Rfx1 and type II nuclear hormone receptors. We found one such target site at a cryptic “shadow” enhancer 7 kilobases (kb) downstream of the Cdx2 gene, where Rfx1 restricts transcriptional activation by FoxA. The Cdx2 shadow enhancer exhibits a subset of regulatory properties of the upstream Cdx2 promoter region. While Cdx2 is ectopically induced in the early metaplastic condition of Barrett's esophagus, its expression is not necessarily present in progressive Barrett's with dysplasia or adenocarcinoma. By contrast, we find that Rfx1 expression in the esophageal epithelium becomes gradually extinguished during progression to cancer, i.e, expression of Rfx1 decreased markedly in dysplasia and adenocarcinoma. We propose that this decreased expression of Rfx1 could be an indicator of progression from Barrett's esophagus to adenocarcinoma and that similar analyses of other transcription factors bound to silent genes can reveal unanticipated regulatory insights into oncogenic progression and cellular reprogramming

Susceptibility of Pancreatic Beta Cells to Fatty Acids Is Regulated by LXR/PPARα-Dependent Stearoyl-Coenzyme A Desaturase

Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARα-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRβ-/- and LXRαβ-/-), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARα agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARα agonists favors their desaturation and subsequent incorporation in neutral lipids

Perioperative fasting time among cancer patients submitted to gastrointestinal surgeries

OBJETIVO Identificar o tempo de jejum perioperatório e sua associação a variáveis pós-operatórias entre pacientes submetidos a cirurgias oncológicas do trato digestório. MÉTODO Estudo de coorte retrospectiva, realizado por meio da consulta a 128 prontuários de pacientes adultos, submetidos a cirurgias oncológicas gastrointestinais. RESULTADOS O tempo total de jejum durante a internação foi em média 107,6 horas. O tempo total de jejum foi associado de forma estatisticamente significante ao número de sintomas pré-operatórios (p=0,000) e pós-operatórios (p=0,007), ao período de internação (p=0,000), à transfusão sanguínea (p=0,013), ao uso de cateter nasogástrico (p=0,001) e nasoentérico (p=0,003), à admissão pós-operatória em terapia intensiva (p=0,002), à morte pós-operatória (p=0,000) e à duração do jejum pré-operatório (p=0,000). CONCLUSÃO A duração do jejum é associada a complicações que afetam a qualidade da recuperação do paciente e o trabalho da enfermagem. A equipe de enfermagem deve estar atenta a esse aspecto, uma vez que, como responsável pela vigilância dos interesses dos pacientes, não deve permitir o prolongamento desnecessário do período de jejum.OBJETIVO Identificar la duración del ayuno perioperatorio entre los pacientes sometidos a cirugías de cáncer gastrointestinal. MÉTODO Estudio de cohorte retrospectivo, por consulta de los registros médicos de 128 pacientes sometidos a cirugías de cáncer gastrointestinal. RESULTADOS La media de la duración total del ayuno fue de 107,6 horas. La duración total del ayuno se asoció significativamente con el número de síntomas presentados antes (p=0,000) y después de la cirugía (p=0,007), la duración de la estancia hospitalaria (p=0,000), transfusión de sangre (p=0,013),tubo nasogástrico (P=0,003), ingreso postoperatorio en la UCI (p=0,002), muerte postoperatoria (p=0,000) y duración del ayuno preoperatorio (p=0,000). CONCLUSIÓN La duración del ayuno se asocia con complicaciones que afectan la calidad de la recuperación postoperatoria de los pacientes y el trabajo de enfermería. El equipo de enfermería debe estar alerta en relación a este aspecto y ser responsable de supervisar el interés de los pacientes, no permitiendo la extensión innecesaria del ayuno.OBJECTIVE To identify the length of perioperative fasting among patients submitted to gastrointestinal cancer surgeries. METHOD Retrospective cohort study, developed by consulting the medical records of 128 patients submitted to gastrointestinal cancer surgeries. RESULTS The mean of total length of fasting was 107.6 hours. The total length of fasting was significantly associated with the number of symptoms presented before (p=0.000) and after the surgery (p=0.007), the length of hospital stay (p=0.000), blood transfusion (p=0.013), nasogastric tube (p=0.001) and nasojejunal tube (p=0,003), postoperative admission at ICU (p=0.002), postoperative death (p=0.000) and length of preoperative fasting (p=0.000). CONCLUSION The length of fasting is associated with complications that affect the quality of the patients’ postoperative recovery and nurses’ work. The nursing team should be alert to this aspect and being responsible for overseeing the patients’ interest, should not permit the unnecessary extension of fasting

Psoríase eritrodérmica com regressão após profilaxia com isoniazida e terapia antidepressiva: relato de caso Erythrodermic psoriasis with regression after prophylaxis with isoniazid and antidepressant therapy: case report

Mulher idosa apresentou psoríase em placas do tipo grave, com tendência eritrodérmica, e foi submetida a tratamento de acordo com o algoritmo consensual (fototerapia, acitretina, ciclosporina). Resultados clínicos insuficientes, recorrência e agravamento do quadro laboratorial orientaram no sentido da introdução de terapia biológica. A avaliação preliminar revelou PPD de 30mm. A resolução completa das lesões se verificou quando realizada profilaxia antituberculose e administrado antidepressivo<br>An 83 year old woman, exhibiting severe psoriasis, was treated conventionally (phototherapy, acitretin, and cyclosporine). After poor clinical results and significant changes in laboratory procedures, those treatments were suspended. She was then being prepared to be submitted to biological treatment, when preliminary results disclosed a 30mm PPD. Complete improvement occurred [only] after introducing prophylactic therapy for tuberculosis and anti-depressive medicatio