Genetic variations in soluble epoxide hydrolase and graft function in kidney transplantation

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are endothelium-derived hyperpolarizing factors that contribute renal protective actions. The aim of this study was to identify the association between genetic variations in soluble epoxide hydrolase (EPHX2, EET-metabolizing enzyme) and kidney allograft dysfunction. MATERIALS AND METHODS: Data from 204 kidney transplant donor-recipient pairs were examined for polymorphisms of exon 8 (R287Q, rs751141 G/A) and 3' untranslated region (3' UTR, rs1042032 A/G) of the EPHX2 gene and correlated with clinical data. RESULTS: The mean duration of follow-up for recipients was 58 +/- 45.3 months who were 39 +/- 11.8 years old at the time of operation and displayed estimated glomerular filtration rate (eGFR) of 68 +/- 16.5 mL/min/1.73 m2 at 1 month after transplantation. AA, AG, and GG genotype frequencies in 3' UTR were 28%, 55%, and 16%, respectively. Twenty-one recipients experienced allograft dysfunction with eGFR <30 mL/min/1.73 m2; 10 had AA genotype of rs1042032 polymorphism (chi-square test; A/A vs A/G+G/G; P = .04). Recipients without rs1042032 polymorphism variant allele showed a significant risk for allograft dysfunction (A/A vs A/G+G/G; P = .04; odds ratio, 2.65; 95% confidence interval [CI], 1.03-6.81). Multivariate analysis of the characteristics of patients using a Cox proportional hazard model showed that the AA genotype of rs1042032 polymorphism was predictive of allograft dysfunction (Hazard Ratio = 3.26; P = .04; 95% CI, 1.08-9.59). CONCLUSION: The present study suggested that the presence of the rs1042032 variant allele in EPHX2 was associated with a protective role for allograft function.     

Rationale for the combination of cryoablation with surgical resection of hepatic tumors

Only 5% to 10% of metastatic and primary liver tumors are amenable to surgical resection. Hepatic cryoablation has increased the number of patients who are suitable for curative treatment. The aim of this study was to evaluate survival and intrahepatic recurrence in patients treated with cryoablation and resection. From June 1994 to July 1999, thirty-eight surgically unresectable patients underwent a total of 42 cryoablative procedures for 65 malignant hepatic lesions. Twenty patients underwent cryoablation alone, and 18 patients were treated with a combination of resection and cryoablation, with a minimum of 18 months’ follow-up. The 38 patients had the following malignancies: primary hepatocellular carcinoma (n = 8) and metastases from colorectal cancer (n = 21), neuroendocrine tumors (n = 3), ovarian cancer (n = 3), leiomyosarcoma (n = 1), testicular cancer (n = 1), and endometrial cancer (n = 1). Patients were evaluated preoperatively with spiral CT scans and intraoperatively with ultrasound examinations for lesion location and cryoprobe guidance. Local recurrence was detected by CT. Major complications included bleeding in three patients and acute renal failure, transient liver insufficiency, and postoperative pneumonia in one patient each. Two patients (5%) died during the early postoperative interval; mean hospital stay was 7.1 days. Median follow-up was 28 months (range 18 to 51 months). Overall survival according to Kaplan-Meier analysis was 82%, 65%, and 54% at 12, 24, and 48 months, respectively. Forty-eight-month survival was not significantly different between those patients undergoing cryoablation alone (64%) and those treated with a combination of resection and cryoablation (42 %). Diseasefree survival at 45 months was 36% for patients undergoing cryoablation plus resection compared to 25% for those undergoing cryoablation alone. Local recurrences were detected at five cryosurgical sites, for a rate of 12% overall (5 of 42), 11% (2 of 18) for patients in the cryoablation plus resection group, and 12% (3 of 24) for those in the cryoablation alone group. For patients with colorectal metastases, survival was 70% at 30 months compared to 33% for hepatocellular cancer and 66% for other types of tumors. Patients with tumors larger than 5 cm or numbering more than three did not have significantly decreased survival. Cryoablation of hepatic tumors is a safe and effective treatment for some patients not amenable to resection. The combination of cryoablation and resection results in survival comparable to that achieved with cryoablation alone. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, San Diego, Calif., May 21–24, 2000.     

Self-catheterization of urinary bladder complicated with extraperitoneal abscess that mimics an infected bladder diverticulum

For patients who are suffering from neurogenic lower urinary tract dysfunction, intermittent urinary catheterization is an efficient way to empty the bladder.¹ However, the method may result in various complications. Herein we present a rare complication of extraperitoneal abscess owing to intermittent urinary catheterization in a 62-year-old male who had cervical spine injury and was treated with intermittent urethral catheterization for neurogenic lower urinary tract dysfunction. Treatment and a literature review are also described.     

柚皮素通过激活mTOR/p70S6K信号通路减轻胰岛素抵抗 并改善H2O2诱导的SH-SY5Y细胞氧化应激损伤

目的：观察柚皮素（naringenin,NAR）对H2O2诱导的SH-SY5Y细胞氧化应激损伤的影响,并探索其机制。方法：通过CCK-8检测细胞存活率,筛选出H2O2的半数致死浓度,用该浓度H2O2同时加入20、40、80 μmol/L柚皮素处理SH-SY5Y细胞4 h,通过CCK-8检测细胞存活率,选择适宜柚皮素浓度。按所选H2O2和柚皮素浓度进行后续实验。将实验分为3组。control组：细胞不进行任何干预处理;H2O2组：只加入600 μmol/L H2O2;H2O2+NAR组：同时加入600 μmol/L H2O2与40 μmol/L柚皮素。4 h后,通过ANNEXIN V-FITC/PI凋亡检测试剂盒检测细胞凋亡率,DCFH-DA荧光探针检测细胞内活性氧（reactive oxy－gen species,ROS）,Western blot检测哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）、核糖体蛋白S6激酶（p70 ribosomal S6 kinase,p70S6K）,以及各自磷酸化形式蛋白[p-mTOR（Ser2448）、p-p70S6K（Thr389）],用胰岛素受体底物-1（insulin receptor substrate 1,IRS1）及其丝氨酸636+639位点磷酸化[p-IRS1（Ser636+Ser639）]蛋白的表达来观察胰岛素抵抗（insulin re－sistance,IR）。结果：H2O2降低SH-SY5Y细胞的存活率,呈剂量依赖性,600 μmol/L浓度为半数致死剂量。柚皮素明显降低了H2O2诱导的SH-SY5Y细胞死亡,最适剂量为40 μmol/L。与control组比,H2O2明显增加了细胞凋亡率、胞内ROS的产生,降低了p-mTOR（Ser2448）、p-p70S6K（Thr389）的表达,增加了p-IRS1（Ser636+Ser639）蛋白的表达（P<0.05）;加入柚皮素后,相对于H2O2组,上述作用明显减弱（P<0.05）。结论：在体外氧化应激模型中,柚皮素能明显降低细胞内ROS的积累,提高细胞的存活率。其机制可能与激活mTOR/p70S6K信号通路、改善IR有关。     

High-grade gliomas and solitary metastases: differentiation by using perfusion and proton spectroscopic MR imaging

PURPOSE: To determine whether perfusion-weighted and proton spectroscopic MR imaging can be used to differentiate high-grade primary gliomas and solitary metastases on the basis of differences in vascularity and metabolite levels in the peritumoral region. MATERIALS AND METHODS: Fifty-one patients with a solitary brain tumor (33 gliomas, 18 metastases) underwent conventional, contrast material--enhanced perfusion-weighted, and proton spectroscopic MR imaging before surgical resection or stereotactic biopsy. Of the 33 patients with gliomas, 22 underwent perfusion-weighted MR imaging; nine, spectroscopic MR imaging; and two underwent both. Of the 18 patients with metastases, 12 underwent perfusion-weighted MR imaging, and six, spectroscopic MR imaging. The peritumoral region was defined as the area in the white matter immediately adjacent to the enhancing (hyperintense on T2-weighted images, but not enhancing on postcontrast T1-weighted images) portion of the tumor. Relative cerebral blood volumes in these regions were calculated from perfusion-weighted MR data. Spectra from the enhancing tumor, the peritumoral region, and normal brain were obtained from the two-dimensional spectroscopic MR acquisition. The Student t test was used to determine if there was a statistically significant difference in relative cerebral blood volume and metabolic ratios between high-grade gliomas and metastases. RESULTS: The measured relative cerebral blood volumes in the peritumoral region in high-grade gliomas and metastases were 1.31 +/- 0.97 (mean +/- SD) and 0.39 +/- 0.19, respectively. The difference was statistically significant (P <.001). Spectroscopic imaging demonstrated elevated choline levels (choline-to-creatine ratio was 2.28 +/- 1.24) in the peritumoral region of gliomas but not in metastases (choline-to-creatine ratio was 0.76 +/- 0.23). The difference was statistically significant (P =.001). CONCLUSION: Although conventional MR imaging characteristics of solitary metastases and primary high-grade gliomas may sometimes be similar, perfusion-weighted and spectroscopic MR imaging enable distinction between the two.     

Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging

Dynamic contrast agent-enhanced perfusion magnetic resonance (MR) imaging provides physiologic information that complements the anatomic information available with conventional MR imaging. Analysis of dynamic data from perfusion MR imaging, based on tracer kinetic theory, yields quantitative estimates of cerebral blood volume that reflect the underlying microvasculature and angiogenesis. Perfusion MR imaging is a fast and robust imaging technique that is increasingly used as a research tool to help evaluate and understand intracranial disease processes and as a clinical tool to help diagnose, manage, and understand intracranial mass lesions. With the increasing number of applications of perfusion MR imaging, it is important to understand the principles underlying the technique. In this review, the essential underlying physics and methods of dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging are described. The clinical applications of cerebral blood volume maps obtained with perfusion MR imaging in the differential diagnosis of intracranial mass lesions, as well as the pitfalls and limitations of the technique, are discussed. Emphasis is on the clinical role of perfusion MR imaging in providing insight into the underlying pathophysiology of cerebral microcirculation.     

Contrast-enhanced power Doppler US: is it useful in the differentiation of gallbladder disease?

Thirteen patients with gallbladder disease underwent power Doppler ultrasound (PDUS) before and after microbubble contrast agent injection. Lesion and liver bed vascularity was evaluated. Pathological diagnoses in nine patients were two acute cholecystitis, four chronic inflammation, one adenoma and two adenocarcinoma. Two cases of cancer were included on clinical and radiological findings. Two cases were excluded because no pathologic diagnosis was available. Liver bed hyperemia was noted only in acute cholecystitis. Contrast-enhanced PDUS was superior to nonenhanced PDUS in the demonstration of vascularity of gallbladder diseases. However, contrast-enhanced PDUS has limited value in the differentiation.     

Abnormal hippocampal structure and function in clinical anxiety and comorbid depression

Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2‐3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation‐structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression—mediated through its impact on abnormal hippocampal threat processing. Collectively, our findings show a strong association between changes in hippocampal microstructure and threat processing, which together may present a common neural pathway to comorbidity of anxiety and depression. © 2016 Wiley Periodicals, Inc.     

Biomolecular Predictors of Urothelial Cancer Behavior and Treatment Outcomes

Urothelial carcinoma of the urinary bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Despite advances in surgical and medical treatment, there has been no change in mortality in UCB over the past decades. Standard pathological features (stage, grade, nodal status) provide only limited information regarding biological potential and clinical behavior. Molecular biomarkers may shed light on important mechanisms of pathogenesis, provide useful additional prognostic information, and serve as targets for therapy. This review summarizes recent advances and the most promising UCB tissue and blood biomarkers of the past few years. We discuss the predictive and prognostic value of biomarkers at different stages of UCB. There is no doubt that a panel of biomarkers will eventually improve our clinical decision-making with regard to treatment and follow-up.     

Risk of Cancer-specific Mortality following Recurrence After Radical Nephroureterectomy

Purpose

To describe the natural history and identify predictors of cancer-specific survival in patients who experience disease recurrence after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).

Methods

Of 2,494 UTUC patients treated with RNU without neoadjuvant chemotherapy, 597 patients experienced disease recurrence. A total of 148 patients (25?%) received adjuvant chemotherapy before disease recurrence. Multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence.

Results

The median time from RNU to disease recurrence was 12?months (interquartile range 5?C22). A total of 491 (82?%) of 597 patients died from UTUC, and 8 patients (1.3?%) died from other causes. The median time from disease recurrence to death of UTUC was 10?months. Actuarial cancer-specific survival estimate at 12?months after disease recurrence was 35?%. On multivariable analysis that adjusted for the effects of standard clinicopathologic characteristics, higher tumor stages [hazard ratio (HR) pT3 vs. pT0?CT1: 1.66, p?=?0.001; HR pT4 vs. pT0?CT1: 1.90, p?=?0.002], absence of lymph node dissection (HR 1.28, p?=?0.041), ureteral tumor location (HR 1.44, p?<?0.0005) and a shorter interval from surgery to disease recurrence (p?<?0.0005) were significantly associated with cancer-specific mortality. The adjusted 6-, 12- and 24-month postrecurrence cancer-specific mortality was 73, 60 and 57?%, respectively.

Conclusions

Approximately 80?% of patients who experience disease recurrence after RNU die within 2?years after recurrence. Patients with non-organ-confined stage, absence of lymph node dissection, ureteral tumor location and/or shorter time to disease recurrence died of their tumor more quickly than their counterparts. These factors should be considered in patient counseling and risk stratification for salvage treatment decision making.