Effects of exercise and nitroprusside on left ventricular ejection dynamics in idiopathic dilated cardiomyopathy

To characterize the abnormal pattern of instantaneous left ventricular (LV) ejection in heart failure, proximal aortic pressure, flow, acceleration, power and dW/dt were measured at rest and during supine bicycle exercise using high-fidelity, catheter-mounted pressure and velocity sensors in 16 patients with idiopathic dilated cardiomyopathy (IDC) and 11 normal control subjects. In patients with IDC, peak flow was lower than normal both at rest (454 +/- 155 vs 649 +/- 168 ml/s, p less than 0.01) and during exercise (569 +/- 213 vs 916 +/- 329 ml/s, p less than 0.01). Peak acceleration, power and dW/dt were also significantly reduced in patients with IDC at rest and during exercise. Time to peak flow (as a fraction of LV ejection time) was consistently prolonged in patients with IDC (rest, 0.40 +/- 0.08 vs 0.29 +/- 0.04; exercise, 0.36 +/- 0.06 vs 0.28 +/- 0.04, both p less than 0.01). Exercise-induced increments in peak flow, power and dW/dt were significantly blunted in patients with IDC. Studies during pacing tachycardia and nitroprusside administration failed to reproduce the abnormalities during exercise in patients with IDC. Thus, the instantaneous flow pulse in heart failure is both diminished in magnitude (decreased stroke volume and peak flow) and abnormal in shape (decrease peak acceleration and delayed time to peak flow). Exercise stress in IDC results in abnormalities of LV performance that can be detected using instantaneous ejection information. These abnormalities are unlikely to be explained by changes in heart rate or loading conditions.     

On the Utility of ToxCast-Based Predictive Models to Evaluate Potential Metabolic Disruption by Environmental Chemicals

Background: Research suggests environmental contaminants can impact metabolic health; however, high costs prohibit in vivo screening of putative metabolic disruptors. High-throughput screening programs, such as ToxCast, hold promise to reduce testing gaps and prioritize higher-order (in vivo) testing.Objectives: We sought to a) examine the concordance of in vitro testing in 3T3-L1 cells to a targeted literature review for 38 semivolatile environmental chemicals, and b) assess the predictive utility of various expert models using ToxCast data against the set of 38 reference chemicals.Methods: Using a set of 38 chemicals with previously published results in 3T3-L1 cells, we performed a metabolism-targeted literature review to determine consensus activity determinations. To assess ToxCast predictive utility, we used two published ToxPi models: a) the 8-Slice model published by Janesick et al. (2016) and b) the 5-Slice model published by Auerbach et al. (2016). We examined the performance of the two models against the Janesick in vitro results and our own 38-chemical reference set. We further evaluated the predictive performance of various modifications to these models using cytotoxicity filtering approaches and validated our best-performing model with new chemical testing in 3T3-L1 cells.Results: The literature review revealed relevant publications for 30 out of the 38 chemicals (the remaining 8 chemicals were only examined in our previous 3T3-L1 testing). We observed a balanced accuracy (average of sensitivity and specificity) of 0.86 comparing our previous in vitro results to the literature-derived calls. ToxPi models provided balanced accuracies ranging from 0.55 to 0.88, depending on the model specifications and reference set. Validation chemical testing correctly predicted 29 of 30 chemicals as per 3T3-L1 testing, suggesting good adipogenic prediction performance for our best adapted model.Discussion: Using the most recent ToxCast data and an updated ToxPi model, we found ToxCast performed similarly to that of our own 3T3-L1 testing in predicting consensus calls. Furthermore, we provide the full ranked list of largely untested chemicals with ToxPi scores that predict adipogenic activity and that require further investigation. https://doi.org/10.1289/EHP6779     

Ethanol potentiates dopamine uptake and increases cell surface distribution of dopamine transporters expressed in SK-N-SH and HEK-293 cells.

Ethanol increases dopaminergic release in the reward and reinforcement areas of the brain. The primary protein responsible for terminating dopamine (DA) neurotransmission is the plasma membrane-bound dopamine transporter (DAT). In vitro electrophysiological and biochemical studies in Xenopus laevis oocytes have previously shown ethanol potentiates DAT function and increases transporter-binding sites. The potentiating effect of ethanol on the transporter is eliminated in Xenopus oocytes by the DAT mutation glycine 130 to threonine. However, ethanol's action on DAT functional regulation has yet to be examined in mammalian cell expression systems. To further understand the molecular mechanisms of ethanol's action on DAT, we determined the direct mechanistic action of short-term (相似文献   

Early recurrence of benign meningioma correlates with expression of mini-chromosome maintenance-2 protein

We have investigated the potential utility of monoclonal antibodies against mini-chromosome maintenance-2 protein (Mcm2) in predicting meningioma recurrence. MCM proteins are members of the DNA-binding prereplicative complex and are essential for eukaryotic DNA replication. They are present throughout the cell cycle, but are down-regulated in quiescence and cell differentiation, making them specific markers of proliferating cells. We analysed 10 benign meningiomas that subsequently recurred within a 5-year period, together with 20 matched non-recurrent benign meningiomas. There was no significant correlation between histological subtype, mitotic count or Ki-67 labelling index and tumour recurrence. We observed that whilst the average Mcm2 labelling index (LI) of the tumour section as a whole (LI(Ave)) is not significantly different between recurrent and nonrecurrent meningiomas, the Mcm2 labelling index in the area of highest proliferative activity within the tumour section (LI(Max)) is significantly higher in recurrent meningiomas (p < 0.0001). Seven out of the 10 recurrent meningiomas displayed a Mcm2 LI((Max) greater than 30%, compared to 0 out of 20 for non-recurrent tumours. In conclusion, these results suggest that analysis of Mcm2 expression may facilitate identification of patients with a high risk of meningioma recurrence, for whom adjuvant radiotherapy may be of benefit.     

A novel immunohistochemical method to estimate cell-cycle phase distribution in archival tissue: implications for the prediction of outcome in colorectal cancer

An immunohistochemical method for assessing cell-cycle phase distribution in colorectal resection specimens would enable phase data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in colorectal cancer. In contrast to flow cytometry, an immunohistochemical method would also allow the phase distribution to be examined within morphologically heterogeneous regions of neoplasms. Paraffin sections of normal colon (n = 25), colonic adenoma (n = 15), and colonic adenocarcinoma (n = 30) were analysed by immunohistochemistry using antibodies against markers of cell-cycle entry, Mcm-2 and Ki67, and putative markers of the cell-cycle phase, cyclins D1 and E (putative markers of G1 phase), cyclin A (S phase), cytoplasmic cyclin B1 (G2 phase), and phosphohistone H3 (M phase). The phase specificity of each marker was assessed by examining the degree of co-expression of adjacent phase markers using double-antibody fluorescence confocal microscopy and by comparison with flow cytometric analysis performed on adjacent tissue sections. The S-phase specificity of detectable cyclin A was also assessed in combination with in situ DNA replication using fluorescence confocal microscopy. All cells expressing phase markers co-expressed Mcm-2. Adjacent phase markers were not significantly co-expressed, confirming the relative specificity of these markers in tissue sections of colon. Cell-cycle phase distribution, calculated by immunohistochemistry, compared well with phase analyses obtained by flow cytometry. No cells expressed cyclin A in the absence of active DNA replication. The S-phase labelling index, as defined by detectable cyclin A expression, showed a positive correlation with the Mcm-2 labelling index and increased in the progression from normal colon to adenocarcinoma. In conclusion, a combination of these cell-cycle phase markers can be used to calculate the distribution of cells throughout each phase of the cell cycle in colorectal tissue sections. Detectable cyclin A can be used as a surrogate marker of S phase and may be of value in predicting prognosis and response to adjuvant therapy.     

Inflammatory markers increase following exposure to radiographic contrast media

PURPOSE: Increased levels of markers of systemic inflammation have been noted in patients following coronary angiographic procedures. The purpose of the present study was to examine the influence of the type of the angiographic procedure as well as the type of radiographic contrast media (RCM) on markers of inflammation. MATERIAL AND METHODS: Thirty-seven patients undergoing diagnostic or interventional coronary angiographic procedures were randomly assigned to receive one of three RCM - an ionic low osmolar agent; a non-ionic, iso-osmotic agent; or a non-ionic, low osmolar agent. Sera were analyzed at baseline (prior to receiving RCM), and at 2, 6 and 24 h thereafter for interleukin (IL)-6 and soluble receptors for tumor necrosis factor alpha (TNFalpha)-1 and TNFalpha- 2. RESULTS: Statistically significant increases over time in each RCM group were noted for IL-6 and both TNFalpha receptors. Comparable increases in inflammatory markers were observed in patients undergoing diagnostic angiography and in patients undergoing an associated coronary intervention. While these markers increased following exposure to both ionic and non-ionic RCM, there was a consistent trend towards lessened marker release with non-ionic RCM. CONCLUSION: Both diagnostic and interventional coronary angiographic procedures are associated with an increase in serum inflammatory markers. While both ionic and non-ionic RCM are associated with increases in serum inflammatory markers, this increase may be attenuated with non-ionic RCM.