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Background: Acute myocardial infarction (AMI) can occur in patients with atherosclerotic disease, with or without plaque rupture. Previous studies have indicated a set of immune responses to plaque rupture. However, the specific circulating immune cell subsets that mediate inflammatory plaque rupture remain elusive. Methods: Ten AMI patients were enrolled in our study (five with and five without plaque rupture; plaque characteristics were identified by optical coherence tomography). By single-cell RNA sequencing, we analyzed the transcriptomic profile of peripheral blood mononuclear cells. Results: We identified 27 cell clusters among 82,550 cells, including monocytes, T cells, NK cells, B cells, megakaryocytes, and CD34+ cells. Classical and non-classical monocytes constitute the major inflammatory cell types, and pro-inflammatory genes such as CCL5, TLR7, and CX3CR1 were significantly upregulated in patients with plaque rupture, while the neutrophil activation and degranulation genes FPR2, MMP9, and CLEC4D were significantly expressed in the intermediate monocytes derived from patients without plaque rupture. We also found that CD4+ effector T cells may contribute to plaque rupture by producing a range of cytokines and inflammatory-related chemokines, while CD8+ effector T cells express more effector molecules in patients without plaque rupture, such as GZMB, GNLY, and PRF1, which may contribute to the progress of plaque erosion. Additionally, NK and B cells played a significant role in activating inflammatory cells and promoting chemokine production in the plaque rupture. Cell--cell communication elaborated characteristics in signaling pathways dominated by inflammatory activation of classical monocytes in patients with plaque rupture. Conclusions: Our studies demonstrate that the circulating immune cells of patients with plaque rupture exhibit highly pro-inflammatory characteristics, while plaque erosion is mainly associated with intermediate monocyte amplification, neutrophil activation, and degranulation. These findings may provide novel targets for the precise treatment of patients with AMI. [ABSTRACT FROM AUTHOR]

Adequate intake of live probiotics is beneficial to human health and wellbeing because they can help treat or prevent a variety of health conditions. However, the viability of probiotics is reduced by the harsh environments they experience during passage through the human gastrointestinal tract (GIT). Consequently, the oral delivery of viable probiotics is a significant challenge. Probiotic encapsulation provides a potential solution to this problem. However, the production methods used to create conventional encapsulation technologies often damage probiotics. Moreover, the delivery systems produced often do not have the required physicochemical attributes or robustness for food applications. Singlecell encapsulation is based on forming a protective coating around a single probiotic cell. These coatings may be biofilms or biopolymer layers designed to protect the probiotic fromthe harsh gastrointestinal environment, enhance their colonization, and introduce additional beneficial functions. This article reviews the factors affecting the oral delivery of probiotics, analyses the shortcomings of existing encapsulation technologies, and highlights the potential advantages of single-cell encapsulation. It also reviews the various approaches available for single-cell encapsulation of probiotics, including their implementation and the characteristics of the delivery systems they produce. In addition, the mechanisms bywhich single-cell encapsulation can improve the oral bioavailability and health benefits of probiotics are described. Moreover, the benefits, limitations, and safety issues of probiotic single-cell encapsulation technology for applications in food and beverages are analyzed. Finally, future directions and potential challenges to the widespread adoption of single-cell encapsulation of probiotics are highlighted. [ABSTRACT FROM AUTHOR]

Background: Coronary biomechanical stress contributes to the plaque rupture and subsequent events. This study aimed to investigate the impact of plaque biomechanical stability on the physiological progression of intermediate lesions, as assessed by the radial wall strain (RWS) derived from coronary angiography. Methods: Patients with at least one medically treated intermediate lesion at baseline who underwent follow-up coronary angiography over 6 months were included. The maximal RWS (RWSmax) of the interrogated lesion was calculated from the baseline angiogram. The primary endpoint was to determine the association between baseline RWSmax and the functional progression of coronary lesions, defined as an increase in the lesion-specific △quantitative flow ratio (L-△QFR, calculated as the absolute change in QFR across the lesion) on serial angiograms. Results: Among 175 lesions in 156 patients, 63 lesions showed an increase in L-△QFR during a median follow-up period of 12.4 months. Baseline RWSmax values were significantly higher in lesions with increased L-△QFR than in those with stabilized or decreased L-△QFR (11.8 [10.7, 13.7] vs.10.8 [9.7, 11.7]; p = 0.001). Baseline RWSmax presented an area under the curve of 0.658 (95% confidence interval [CI]: 0.572–0.743, p < 0.001) for the prediction of increased L-△QFR. After full adjustment for clinical and angiographic factors, a high RWSmax (>12) was found to be an independent predictor of functional lesion progression (odds ratio: 2.871, 95% CI: 1.343–6.138, p = 0.007). Conclusions: A high RWSmax calculated from baseline angiograms was independently associated with the subsequent physiological progression in patients with intermediate coronary lesions. [ABSTRACT FROM AUTHOR]

Triticale (× Triticosecale Wittmack) is a hybrid cereal prepared by crossing wheat and rye. Triticale grain contains substances that have a positive effect on reducing the risk of cardiovascular disease, obesity, cancer, and type 2 diabetes, as well as increasing body's immune response and intestinal function, which warrants a need for greater attention to research on triticale crop's nutritional composition. This review covers the most recent research on the nutritional composition of triticale grain in comparison to other cereals, its role in the food industry, and its usage as a food, providing a scientific foundation for triticale's further development as a sustainable crop. Due to the wide variety of chemical compounds revealed in triticale grain, it has the potential to be utilised as a substitute cereal for various food and beverages. [ABSTRACT FROM AUTHOR]

Acute coronary syndrome (ACS) is the most severe form of ischemic heart disease. Although it is caused by atherosclerotic plaque thrombosis or nonatherosclerotic causes, its pathophysiological mechanism of ACS is not fully understood, and its concept is constantly updated and developed. At present, the main pathophysiological mechanisms include plaque rupture, plaque erosion, calcified nodules (CN) and non-atherosclerotic causes such as coronary vasospasm and myocardial bridging (MB). These mechanisms may overlap and coexist in some ACS patients. Therefore, the pathophysiological mechanism of ACS is complex, and is of great significance for the diagnosis and treatment of ACS. This review will discuss the pathophysiological mechanisms of ACS to provide new thoughts on the pathogenesis, diagnosis and treatment of ACS. [ABSTRACT FROM AUTHOR]

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Tissue damage in diabetes is at least partly due to elevated reactive oxygen species production by the mitochondrial respiratory chain during hyperglycemia. Sustained hyperglycemia results in mitochondrial dysfunction and the abnormal expression of mitochondrial genes, such as NADH: Ubiquinone oxidoreductase subunit A13 (NDUFA13). Metformin, an AMP‑activated protein kinase (AMPK) activator, protects cardiomyocytes from oxidative stress by improving mitochondrial function; however, the exact underlying mechanisms are not completely understood. The aim of the present study was to investigated the molecular changes and related regulatory mechanisms in the response of H9C2 cardiomyocytes to metformin under high glucose conditions. H9C2 cells were subjected to CCK‑8 assay to assess cell viability. Reactive oxygen species generation was measured with DCFH‑DA assay. Western blotting was used to analyze the expression levels of NDUFA13, AMPK, p‑AMPK and GAPDH. Reverse transcription‑quantitative PCR was used to evaluate the expression levels of mitochondrial genes and transcription factors. It was observed that metformin protected H9C2 cardiomyocytes by suppressing high glucose (HG)‑induced elevated oxidative stress. In addition, metformin stimulated mitochondrial biogenesis, as indicated by increased expression levels of mitochondrial genes (NDUFA1, NDUFA2, NDUFA13 and manganese superoxide dismutase) and mitochondrial biogenesis‑related transcription factors [peroxisome proliferator‑activated receptor‑gamma coactivator‑1α, nuclear respiratory factor (NRF)‑1, and NRF‑2] in the metformin + HG group compared with the HG group. Moreover, metformin promoted mitochondrial NDUFA13 protein expression via the AMPK signaling pathway, which was abolished by pretreatment with the AMPK inhibitor, Compound C. The results suggested that metformin protected cardiomyocytes against HG‑induced oxidative stress via a mechanism involving AMPK, NDUFA13 and mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Objective: Ceramides are associated with coronary plaque vulnerability. We aim to investigate the potential diagnostic value of ceramides for acute coronary syndrome (ACS) in Chinese patients with chest pain. Design: Prospective observational survey. Setting: Shanghai, China, 2016-2017. Participants: A total of 2773 patients with chest pain from four hospitals in Shanghai, China, between August 2016 and October 2017. Main outcome measures: Performance of metabolites model in detection of ACS cases including ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina. Results: Plasma levels of 12 ceramide molecules and corresponding ratios were compared between patients diagnosed with ACS and those without. Cer(d18:1/24:1(15Z))/Cer(d18:1/24:0) ratio, Cer(d18:1/14:0) and Cer(d18:1/22:0) were independent predictors of ACS after adjustment of traditional risk factors and high-sensitivecardiac troponin T. Receiver operating characteristic curve analysis showed a significant improvement in detecting ACS in the multivariable model with ceramides compared with that without (0.865 (0.840 to 0.889) vs 0.808 (0.776 to 0.841), p<0.001). Conclusion: Distinct plasma ceramides are independent diagnostic predictors of ACS among patients with chest pain. Ceramides together with high-sensitive troponin and traditional factors showed great potential in identifying ACS among patients with chest pain. [ABSTRACT FROM AUTHOR]

The differences in angiographic characteristics and cardiovascular (CV) risk factors between coronary artery aneurysm (CAA) and coronary artery ectasia (CAE) have not been compared systematically. Of 10 876 patients undergoing coronary angiography, patients with CAA (n = 85) and CAE (n = 51) were screened. The prevalence of CAA was greater than that of CAE (P < .05). The right coronary artery was the most involved (70.6%) in CAE compared with left circumflex (52.9%) and left anterior descending (41.2%). Coronary artery aneurysm coexisted with coronary artery disease (CAD) more frequently than CAE (P = .002), and the modified Gensini score of CAA was also higher than that of CAE (P < .001). The average maximum diameter was smaller, and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count was lower in CAA than CAE in all 3 coronary arteries (P < .001). Multivariate analysis showed that hyperlipidemia (P = .02), smoking (P = .04), and family history of CAD (P = .02) were the independent variables most strongly associated with CAA, but not CAE. This study suggests that there are significant differences in coronary angiographic characteristics and CV risk factors between CAA and CAE. [ABSTRACT FROM AUTHOR]

Introduction Available data show that approximately 8%-18% of patients with primary hypertension will develop resistant hypertension. In recent years, catheter-based renal denervation (RDN) has emerged as a potential treatment option for resistant hypertension. A number of observational studies and randomised controlled trials among non-Chinese patients have demonstrated its potential safety and efficacy. Methods and analysis This is a multicentre, randomised, open-label, parallel-group, active controlled trial that will investigate the efficacy and safety of a 5F saline-irrigated radiofrequency ablation (RFA) used for RDN in the treatment of Chinese patients with resistant hypertension. A total of 254 patients who have failed pharmacological therapy will be enrolled. Eligible subjects will be randomised in a 1:1 ratio to undergo RDN using the RFA plus antihypertensive medication or to receive treatment with antihypertensive medication alone. The primary outcome measure is the change in 24 hours average ambulatory systolic blood pressure from baseline to 3 months, comparing the RDN-plus-medication group with the medication-alone group. Important secondary endpoints include the change in office blood pressure from baseline to 6 months after randomisation. Safety endpoints such as changes in renal function will also be evaluated. The full analysis set, according to the intent-to-treat principle, will be established as the primary analysis population. Ethics and dissemination All participants will provide informed consent; the study protocol has been approved by the Independent Ethics Committee for each site. This study is designed to investigate the efficacy and safety of RDN using a 5F saline microirrigated RFA. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of resistant hypertension in China. Trial registration ClinicalTrials.gov ID: NCT02900729; pre-results. [ABSTRACT FROM AUTHOR]

The proliferation of knowledge-sharing communities has generated large amounts of data. Prominent examples of how user-generated content can be harnessed include IBM's Watson question answering sytem and Apple's Siri, the question answering application in iPhones. Facing such massive data, user authority ranking is important to the development of question answering and other e-commerce services. In this study, we propose three probabilistic models to rank the user authority of each question. Compared to the existing approaches focused on the user relationship primarily, our method is more effective because we consider the link structure and topical similarities between users and questions simultaneously. We use a real-world dataset from Zhihu, a popular community question answering website in China to conduct experiments. Experimental results show that our model outperforms other baseline methods in ranking the user authority. [ABSTRACT FROM AUTHOR]

The proliferation of knowledge-sharing communities has generated large amounts of data. Prominent examples of how user-generated content can be harnessed include IBM's Watson question answering sytem and Apple's Siri, the question answering application in iPhones. Facing such massive data, user authority ranking is important to the development of question answering and other e-commerce services. In this study, we propose three probabilistic models to rank the user authority of each question. Compared to the existing approaches focused on the user relationship primarily, our method is more effective because we consider the link structure and topical similarities between users and questions simultaneously. We use a real-world dataset from Zhihu, a popular community question answering website in China to conduct experiments. Experimental results show that our model outperforms other baseline methods in ranking the user authority. [ABSTRACT FROM AUTHOR]

Background: This study was designed to investigate the effect of clopidogrel-related gene polymorphisms on platelet reactivity and clinical outcome in Chinese Han patients. Materials and Methods: Three hundred and thirty-six percutaneous coronary intervention - treated patients were recruited and followed for 1 year. Blood samples were collected from all patients for DNA genotyping. The platelet reactivity unit was measured by the VerifyNow technique. The CYP2C19*2, CYP2C19*3, CYP2C19*17, ATP-binding cassette subfamily B member 1, ITGB3, CYP2C9*3, CYP2B6*9, and P2Y12 alleles were assessed. Results: The clinical endpoints were related to previous heart disease history (11.90% vs. 28.57%, P = 0.017), stroke (12.24% vs. 16.67%, P = 0.039), and diabetes (27.55% vs. 52.38%, P = 0.047). High on-treatment platelet reactivity (HTPR) was frequent in advanced age (P = 0.019), male gender (P = 0.016), hypertension (P = 0.033), and chronic renal failure (P = 0.040). There were more endpoints in the CYP2C19*2 and P2Y12 mutant carriers (76.19% vs. 43.20%, P < 0.001; 50.00% vs. 35.71%, P = 0.001, respectively), whereas fewer in the CYP2C19*17 mutant carriers (11.90% vs. 56.46%, P = 0.001). CYP2C19*2 and P2Y12 polymorphism manifested HTPR (194.25 ± 45.91 vs. 151.38 ± 58.14, P < 0.001; 180.33 ± 67.25 vs. 161.89 ± 56.49, P = 0.008, respectively), whereas CYP2C19*17 mutant improved platelet reactivity (97.17 ± 45.38 vs. 169.08 ± 57.15, P = 0.003). However, there were no further cardiovascular deaths in endpoint patients. Conclusion: In Han Chinese people of mainland China, clopidogrel-related gene polymorphisms are related to variable platelet reactivity after clopidogrel maintenance dosing, which influences major adverse cardiovascular events, without an effect on cardiac death. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the relevance of the gap junction protein connexin Cx43 in coronary artery smooth muscle cell (SMC) heterogeneity and coronary artery restenosis. SMCs were isolated from the coronary artery of 3-month-old pigs using enzymatic digestion. Two distinct SMC populations were isolated: Rhomboid (R) and spindle-shaped (S) cells. S-SMCs exhibited relatively lower rates of proliferation, exhibiting a classic ''hills-and valleys'' growth pattern; R-SMCs displayed increased proliferation rates, growing as mono- or multi-layers. Immunofluorescent staining, polymerase chain reaction and western blotting were used to assess the expression of Cx40 and Cx43 in SMCs. For further evaluation, cultured SMCs were treated with 10 ng/ml platelet-derived growth factor (PDGF)-BB with or without the gap junction blocker 18α-glycyrrhetinic acid. Stent-induced restenosis was assessed in vivo. Different expression patterns were observed for Cx40 and Cx43 in R- and S-SMCs. Cx40 was the most abundant Cx in S-SMCs, whereas CX43 was identified at relatively higher levels than Cx40 in R-SMCs. Notably, PDGF-BB converted S-SMCs to R-SMCs, with increased Cx43 expression, while 18α-glycyrrhetinic acid inhibited the PDGF-BB-induced phenotypic alterations in S-SMCs. Additionally, restenosis was confirmed in pigs 1-month subsequent to stent placement. R-SMCs were the major cell population isolated from stent-induced restenosis artery tissues, and exhibited markedly increased Cx43 expression, in accordance with the in vitro data described above. In conclusion, the phenotypic transformation of coronary artery SMCs is closely associated with Cx43, which is involved in restenosis. These observations provide a basis for the use of Cx43 as a novel target in restenosis prevention. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/ PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ- P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/ PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions. [ABSTRACT FROM AUTHOR]

We previously demonstrated that inhibitor κB kinase 2 (IKK2) is a myosin light chain kinase (MLCK). In the present study, we assess whether the prototypical activator of IKK2 tumor necrosis factor-α (TNF-α) regulates the MLCK activity of IKK2 and thus MLC phosphorylation in vascular smooth muscle cells (VSMCs). Kinase activity assay revealed that TNF-α downregulated the MLCK activity of IKK2 in human VSMCs (HVSMCs). However, Western blot analysis did not demonstrate a significant effect of TNF-α on MLC phosphorylation in HVSMCs, and myograph analysis did not reveal a significant effect of TNF-α on the contraction of the aorta from Sprague-Dawley rats and C57Bl/6j mice, suggesting a dual regulation of MLC phosphorylation by TNF-α. Confirming this notion, TNF-α significantly increased MLC phosphorylation in IKK2-/- but not wild-type cells. Furthermore, our results show that TNF-α increased GTP-bound RhoA and MLC phosphatase subunit MYPT1 phosphorylation and markedly reduced MLC phosphorylation in the presence of Rho-kinase inhibitor Y-27632, suggesting that downregulation of MLCK activity of IKK2 by TNF-α is antagonized by simultaneous RhoA/Rho-kinase activation. These results indicate that TNF-α dually regulates MLC phosphorylation through both IKK2 and RhoA/Rho-kinase pathways. [ABSTRACT FROM AUTHOR]

First published March 27, 2013; doi:10.1152/ajpregu.00082.2013.--An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuronspecific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM- 087, Vaprisol, 22 ng/h) or the V2-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (～15 mmHg) hypertension in sRA mice. Abdominal aortas and secondorder mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V1A receptor mRNA, but no significant changes in V2 receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brainspecific hyperactivity of the RAS and suggest a primary role of V2 receptors. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR-/-), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR-/- vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensinconverting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Receptor activity-modifying proteins (RAMPs) 1, 2, and 3 are unusual accessory proteins that dictate the binding specificity of two G protein-coupled receptors involved in energy homeostasis: calcitonin gene-related peptide (CGRP) and amylin receptors. These proteins are expressed throughout the central nervous system (CNS), including in the brain regions involved in the regulation of energy homeostasis, but the significance of CNS RAMPs in the control of energy balance remains unknown. RESEARCH DESIGN AND METHODS--To examine the functional significance of modulating neuronal RAMP1, we assessed the effect of overexpressing human RAMP1 (hRAMP1) in the CNS on body energy balance. RESULTS--Nestin/hRAMP1 transgenic mice have a remarkably decreased body weight associated with reduced fat mass and circulating leptin levels. The transgenic mice exhibited higher energy expenditure as indicated by increased oxygen consumption, body temperature, and sympathetic tone subserving brown adipose tissue (BAT). Consistent with this, the nesti/hRAMP1 transgenic mice had elevated BAT mRNA levels of peroxisome proliferator-activated receptor γ coactivator 1α and uncoupling protein 1 mid 3, and these changes can be reversed by chronic blockade of sympathetic nervous system signaling. Furthermore, metabolic response to amylin was enhanced in the nestin/hRAMP1 mice whereas the response to CGRP was blunted, possibly the result of higher expression of CGRP in the CNS. CONCLUSIONS--These data demonstrate that CNS RAMP1 plays a pivotal role in the regulation of energy homeostasis by promoting energy expenditure. [ABSTRACT FROM AUTHOR]

Aims: We sought to determine whether repeat administration of bone marrow mononuclear cells (BMC) can improve left ventricular function compared with a single infusion in patients with large acute myocardial infarction (AMI). [ABSTRACT FROM PUBLISHER]

We previously generated transgenic mice carrying a large P1 artificial chromosome (PAC16O) encompassing a 160-kb segment containing the human renin gene, two upstream genes, and one downstream gene. We also previously generated mutant PAC 160 constructs lacking the distal enhancer and concluded it is required to maintain baseline expression of human renin, but is not required for tissue-specific, cell-specific, and regulated expression of renin in vivo. We now report two additional transgenic lines carrying random truncations of PAC 160 upstream of the renin gene. Southern and PCR mapping studies indicate that the truncation break points in the two lines are located ∼10.4 and 2.5 kb upstream of the renin gene causing a deletion of all DNA upstream of the break. We tested the hypothesis that large-scale deletion of DNA upstream of the human renin gene including the enhancer would cause dysregulation of human renin expression. Phenotypically, these truncations cause a severe dysregu- lation of human renin expression, but remarkably, a preservation of the normal tissue-specific expression of the human ethanolamine kinase 2 (ETNK2) gene which lies immediately downstream of renin. Several functional binding sites for CTCF, a mammalian insulator protein, were identified in and around the renin and ETNK2 loci by gel shift and chromatin immunoprecipitation. We conclude that there are sequences in and around the renin and ETNK2 loci which act as boundaries between neighboring genes which insulate them from each other. The study illustrates the value of taking a much wider genomic perspective when studying mechanisms regulating gene expression. [ABSTRACT FROM AUTHOR]

Abstract  Accurate length measurements by intravascular ultrasound (IVUS) are necessary for stent length selection and for IVUS volumetric analysis. The comparative accuracy of commercially available transducer pullback systems––a necessity for accurate IVUS length and volume measurements––has never been studied. We evaluated the accuracy of four IVUS pullback systems by studying 180 patients (45 in each group) who had been treated with a single stent of known length. Stented lesions were located in the left anterior descending artery (n = 77), left circumflex artery (n = 41), right coronary artery (n = 41), left main (n = 2), and saphenous vein grafts (n = 19). The known lengths of implanted stents ranged from 8 to 33 mm. The correlations between known stent length and IVUS-measured stent length in each group were 0.92 for CVIS, 0.83 for BSC Galaxy, 0.63 for Endosonics TrackBack, and 0.69 for Volcano Model R-l00 research pullback device, respectively. Furthermore, the absolute value of the difference between the two measurements was 9.1 � 13.1%, 8.8 � 10.2%, 18.6 � 21.5%, and 17.5 � 31.4%, respectively. With the Volcano Model R-l00 research pullback device, there were 3 extreme outliers; if these three outliers were excluded, then the correlation improved from 0.69 to 0.91; and the absolute deviation from known stent length improved from 17.5 � 31.4% to 9.7 � 8.3%. Thus, there is a significant variation in length measurement accuracy among IVUS pullback devices. This should be taken into account both clinically and when planning scientific studies. [ABSTRACT FROM AUTHOR]

In the brain, angiotensinogen (AGT) is primarily expressed in astrocytes; brain ANG II derived from locally produced AGT has been shown to influence blood pressure. To better understand the molecular basis of AGT expression in the brain, we identified a human astrocytoma cell line, CCF-STTG1, that expresses endogenous AGT mRNA and produces AGT protein. Studies examining CCF-STTG1 cell AGT after N- and O-glycosidase suggest that AGT may not be posttranslationally modified by glycosylation in these cells as it is in plasma. Small amounts of AGT (5% of HepG2) were detected in the culture medium, suggesting a low rate of AGT secretion. Immunocytochemical examination of AGT in CCF-STTG1 cells revealed mainly nuclear localization. Although this has not been previously reported, it is consistent with nuclear localization of other serpin family members. To examine this further, we generated a fusion protein consisting of green fluorescent protein (GFP) and human AGT and examined subcellular localization by confocal microscopy after confirming expression of the fusion protein by Western blot. In CCF-STTG1 cells, a control GFP construct lacking AGT was mainly localized in the cytoplasm, whereas the GFP-AGT fusion protein was primarily localized in the nucleus. To map the location of a potential nuclear localization signal, overlapping 500-bp fragments of human AGT cDNA were fused in frame downstream of GFP. Although four of the fusion proteins exhibited either perinuclear or cytoplasmic localization, one fusion protein encoding the COOH terminus of AGT was localized in the nucleus. Importantly, nuclear localization of human AGT was confirmed in primary cultures of glial cells isolated from transgenic mice expressing the human AGT under the control of its own endogenous promoter. Our results suggest that AGT may have a novel intracellular role in the brain apart from its predicted endocrine function. [ABSTRACT FROM AUTHOR]