Analyses of chromosome copy number and expression level of four genes in the ciliate Chilodonella uncinata reveal a complex pattern that suggests epigenetic regulation

Exogenous wild-type p53 (wt-p53) tumor suppression increases the sensitivity of tumor cells to radiotherapy and chemotherapy. An iodized oil emulsion was used as a p53 vector for intra-arterial gene delivery to treat hepatic tumors. Whether the chemotherapeutic agent or the iodized oil affects exogenous wt-p53 activity remains poorly understood. In the present study, the early therapeutic response of rAd/p53, combined with 5-fluorouracil (5-FU) or with iodized oil, was observed in a human colon cancer model. Allograft models in 82 nude mice with human colon carcinoma SW480 were divided randomly into four groups and administered with physiologic saline, rAd/p53, rAd/p53+5-FU, and rAd/p53+iodized oil by intratumoral injection. At 24, 48, 72, 120, and 168 h after treatment, p53 expression, the Ki-67 index (KI), and the degree of tumor necrosis were assessed. The p53 expression and tumor necrosis in the therapeutic groups were higher than those in the control group. p53 expression reached its peak at 120 h in the rAd/p53 group, at 72 h in the rAd/p53+5-FU group, and at 48 h in the rAd/p53+iodized oil group. The p53 expression in the rAd/P53+5-FU group and the iodized oil group was significantly higher than those in the rAd/P53 group at 24 and 48 h. The results revealed that tumor necrosis is positively correlated with p53 expression. The KI of the rAd/p53+5-FU group increased significantly at 24 h. 5-FU and iodized oil increase the anticancer effect of rAd/p53, and 5-FU combined with rAd/p53 has a synergistic anticancer effect.     

Congenital heart defect and mental retardation in a patient with a 13q33.1-34 deletion

13q deletion syndrome is a rare genetic disorder caused by deletions of the long arm of chromosome 13. Patients with 13q deletion display a variety of phenotypic features. We describe a one-year-old female patient with congenital heart defects (CHD), facial anomalies, development and mental retardation. We identified a 12.75Mb deletion in chromosome region 13q33.1-34 with high resolution SNP Array (Human660W-Quad, Illumina, USA). This chromosome region contains about 55 genes, including EFNB2, ERCC5, VGCNL1, F7, and F10. Comparing our findings with previously reported 13q deletion patients with congenital heart defects, we propose that the 13q33.1-34 deletion region might contain key gene(s) associated with cardiac development. Our study also identified a subclinical deficiency of Factors VII and X in our patient with Group 3 of 13q deletion syndrome.     

Myocardial gene expression profiling of rewarming shock in a rodent model of accidental hypothermia

Background

Severe accidental hypothermia represents a cardiovascular emergency associated with high mortality and poor recovery of cardiac function. The biochemical changes occurring within the heart during the development of hypothermia and subsequent resuscitation are not known.

Methods

By mRNA expression profiling, we have characterized gene expression changes occurring within the myocardium in an intact rat model of accidental hypothermia during cooling to a core temperature of 15 °C and subsequent rewarming to 37 °C. During the rewarming phase, these animals develop a profound low-output cardiac failure.

Results

Hypothermia induces expression of known mediators of thermotolerance, including heat-shock protein 70 and several factors involved in protection against apoptotic cell death. Upregulation of genes involved in autophagy and increased abundance of autophagosomal vesicles suggest involvement of autophagic degeneration in the development of myocardial dysfunction occurring during rewarming from hypothermia. Rewarming from hypothermia also induces expression of several pro-inflammatory genes involved in the nuclear factor kappa B (NFκB) signaling cascade.

Conclusions

Our data demonstrate that rewarming from hypothermia is associated with the induction of a cellular stress–response, including upregulation of autophagy and activation of pro-inflammatory signaling cascades. These data provide a framework for understanding the molecular changes that occur during induction of and rewarming from severe hypothermia, and identifies potential targets for cardioprotective interventions in resuscitation of victims of hypothermia.     

Association between ABCB1 gene polymorphisms and fentanyl's adverse effects in Turkish patients undergoing spinal anesthesia

The ATP-binding cassette transporter (ABCB1) gene product, P-glycoprotein plays an important role in the prevention of intracellular accumulation of potentially toxic substances and metabolites in various tissues. Single nucleotide polymorphisms in this gene are claimed to be correlated with changes in the function of P-glycoprotein. There is evidence that fentanyl, may be a substrate for P-glycoprotein. The aim of the study was to assess whether an association exists between ABCB1 gene polymorphism and early respiratory and sedative adverse effects of intravenous fentanyl in Turkish patients who underwent spinal anesthesiaIn all 83 unrelated Turkish patients were enrolled in this study. In this study, spinal anesthesia was provided and a single dose of intravenous fentanyl (2.5 μg.kg⁻¹) at the beginning of surgery was used as a sedative agent. Bispectral index, respiration rate and peripheral oxygen saturation were measured continuously and recorded throughout the study.The allele and genotype frequencies were similar to previous data from Turkish population.Respiratory rate (RR) and SpO₂ parameters of the patients did not show any significant difference according to the genotype distribution for C1236T and C3435T SNPs. Fentanyl-induced decrease in respiration rate was most remarkable at 15 min (23%) in CC genotype of C1236T, whereas in TT genotype of C3435T (18%) polymorphism. SpO₂ parameters in allele distribution were also not significant among the groups (p = 0.374, p = 0.985, respectively). For the C1236T polymorphism, patients carrying T allele showed a significant decrease in pH, and a significant increase in pCO₂ (p < 0.001).ABCB1 polymorphisms did not seem to have a significant effect on sedation and respiratory depression caused by intravenous fentanyl in spinal anesthesia in Turkish patients.     

Differences of cardiac output measurements by open-circuit acetylene uptake in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: a cohort study

Background

As differences in gas exchange between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) have been demonstrated, we asked if cardiac output measurements determined by acetylene (C₂H₂) uptake significantly differed in these diseases when compared to the thermodilution technique.

Method

Single-breath open-circuit C₂H₂ uptake, thermodilution, and cardiopulmonary exercise testing were performed in 72 PAH and 32 CTEPH patients.

Results

In PAH patients the results for cardiac output obtained by the two methods showed an acceptable agreement with a mean difference of -0.16 L/min (95% CI -2.64 to 2.32 L/min). In contrast, the agreement was poorer in the CTEPH group with the difference being -0.56 L/min (95% CI -4.96 to 3.84 L/min). Functional dead space ventilation (44.5 ± 1.6 vs. 32.2 ± 1.4%, p < 0.001) and the mean arterial to end-tidal CO₂ gradient (9.9 ± 0.8 vs. 4.1 ± 0.5 mmHg, p < 0.001) were significantly elevated among CTEPH patients.

Conclusion

Cardiac output evaluation by the C₂H₂ technique should be interpreted with caution in CTEPH, as ventilation to perfusion mismatching might be more relevant than in PAH.     

Epistatic interactions in idiopathic pulmonary arterial hypertension

BACKGROUND:

Idiopathic pulmonary arterial hypertension (IPAH) is a poorly understood complex disorder, which results in progressive remodeling of the pulmonary artery that ultimately leads to right ventricular failure. A two-hit hypothesis has been implicated in pathogenesis of IPAH, according to which the vascular abnormalities characteristic of PAH are triggered by the accumulation of genetic and/or environmental insults in an already existing genetic background. The multifactor dimensionality reduction (MDR) analysis is a statistical method used to identify gene–gene interaction or epistasis and gene–environment interactions that are associated with a particular disease. The MDR method collapses high-dimensional genetic data into a single dimension, thus permitting interactions to be detected in relatively small sample sizes.

AIM:

To identify and characterize polymorphisms/genes that increases the susceptibility to IPAH using MDR analysis.

MATERIALS AND METHODS:

A total of 77 IPAH patients and 100 controls were genotyped for eight polymorphisms of five genes (5HTT, EDN1, NOS3, ALK-1, and PPAR-γ2). MDR method was adopted to determine gene–gene interactions that increase the risk of IPAH.

RESULTS:

With MDR method, the single-locus model of 5HTT (L/S) polymorphism and the combination of 5HTT(L/S), EDN1(K198N), and NOS3(G894T) polymorphisms in the three-locus model were attributed to be the best models for predicting susceptibility to IPAH, with a P value of 0.05.

CONCLUSION:

MDR method can be useful in understanding the role of epistatic and gene–environmental interactions in pathogenesis of IPAH.     

野战微创介入方舱内实施对脾脏损伤的快速救治实验

目的:探讨在战争或自然灾害等野战特定条件下,使用野战微创介入方舱,现场对脾脏创伤实施快速微创介入栓塞救治的可行性及效果,形成介入方舱内对脾脏进行快速介入栓塞救治的流程。方法:野战条件下,展开野战介入方舱,在血管造影机下对大动物(狗)脾动脉进行血管内穿刺造模,建立脾动脉损伤模型,按照方舱内快速微创介入救治的流程,对脾动脉受损伤的动物(狗)实施腹部内受损脾动脉的栓塞止血术式。结果:按照设定的预案,对脾损伤的模型动物实施早期介入栓塞脾动脉止血治疗,全部实验动物2周存活率为100%。结论:野战条件下,考虑到转运风险时或者伤情十分紧急时,靠近事发现场展开野战微创介入方舱,对腹部脾脏损伤开展紧急介入栓塞止血救治,不仅可为病人后续的治疗争取宝贵时间,大幅降低一线伤死率,而且脾脏的保全也提高伤员愈后的生活质量。     

Simulation of blood flow in a small-diameter vascular graft model with a swirl (spiral) flow guider

Small-diameter vascular grafts are in large demand for coronary and peripheral bypass procedures, but present products still fail in long-term clinical application. In the present communication, a new type of small-diameter graft with a swirl flow guider was proposed to improve graft patency rate. Flow pattern in the graft was simulated numerically and compared with that in a conventional graft. The numerical results revealed that the swirl flow guider could indeed make the blood flow rotate in the new graft. The swirling flow distal to the flow guider significantly altered the flow pattern in the new graft and the ve- locity profiles were re-distributed. Due to the swirling flow, the blood velocity near the vessel wall and wall shear rate were greatly enhanced. We believe that the increased blood velocity near the wall and the wall shear rate can impede the occurrence of acute thrombus formation and intimal hyperplasia, hence can improve the graft patency rate for long-term clinical use.     

Differential cardiovascular effects of synthetic peptides derived from endomorphin-1 in anesthetized rats

Previously, five synthetic peptides derived from endomorphin-1 (Tyr¹-Pro²-Trp³-Phe⁴-NH₂, EM-1), including Tyr-d-Ala-Trp-p-Cl-Phe-NH₂ (HDAPC), Tyr-d-Ala-Trp-Phe-NH₂ (HDADC), N-amidino-Tyr-d-Ala-Trp-p-Cl-Phe-NH₂ (GDAPC), N-amidino-Tyr-d-Ala-Trp-Phe-NH₂ (GDADC) and N-amidino-Tyr-d-Pro-Gly-Trp-p-Cl-Phe-NH₂ (GBDPC), were described to elicit analgesia by subcutaneous administration with enhanced metabolic stabilities. To further our knowledge of the influences of particular modification on the pharmacological activities of EM-1, the present study was undertaken to investigate cardiovascular effects of these peptides in anesthetized rats by intravenous injection. Our results showed that the four d-Ala-containing peptides decreased the systemic arterial pressure (SAP) and heart rate (HR) through a naloxone-sensitive mechanism. Different patterns, potencies and durations of cardiovascular effects were observed among these peptides. When compared to EM-1, the hemodynamic responses to these four tetrapeptides were significantly lower in magnitude but much longer in duration. Surprisingly, intravenous administration of the only pentapeptide GBDPC produced fairly prolonged hypertensive and tachycardiac effects, which was naloxone-insensitive, thus providing evidence that changes in the primary structure of a peptide can profoundly affect its pharmacological activity. Comparisons of the cardiovascular effects between these peptides showed that each modification introduced into EM-1, including N-amidination, chloro-halogenation and unnatural amino acid substitution, played a role in the influence on the cardiovascular regulation of these peptides.