Doxorubicin Detoxification in Healthy Organs Improves Tolerability to High Drug Doses for Enhanced Antitumor Therapy.

With its well-documented toxicity, the use of doxorubicin (Dox) for cancer treatment requires trade-offs between safety and effectiveness. This limited use of Dox also hinders its functionality as an immunogenic cell death inducer, thus impeding its usefulness for immunotherapeutic applications. Here, we develop a biomimetic pseudonucleus nanoparticle (BPN-KP) by enclosing GC-rich DNA within erythrocyte membrane modified with a peptide to selectively target healthy tissue. By localizing treatment to organs susceptible to Dox-mediated toxicity, BPN-KP acts as a decoy that prevents the drug from intercalating into the nuclei of healthy cells. This results in significantly increased tolerance to Dox, thereby enabling the delivery of high drug doses into tumor tissue without detectable toxicity. By lessening the leukodepletive effects normally associated with chemotherapy, dramatic immune activation within the tumor microenvironment was also observed after treatment. In three different murine tumor models, high-dose Dox with BPN-KP pretreatment resulted in significantly prolonged survival, particularly when combined with immune checkpoint blockade therapy. Overall, this study demonstrates how targeted detoxification using biomimetic nanotechnology can help to unlock the full potential of traditional chemotherapeutics.

Two in One: Echocardiographic Features of Right-Ventricular Diverticulum and Left-Ventricular Aneurysm in the Same Patient.

Ventricular diverticulum is a rare congenital heart defect that is usually found incidentally upon imaging, such as 2-dimensional transthoracic echocardiogram. We report a case in which an isolated right-ventricular diverticulum and a left-ventricular aneurysm were both found on transthoracic echocardiogram in the setting of a pulmonary embolism. This case highlights how to distinguish between an aneurysm and a diverticulum based on wall motion on echocardiogram, as well as potential complications that may arise from either anomaly.

La présence d'un diverticule ventriculaire est une malformation cardiaque congénitale rare qui est habituellement détectée par accident lors d'un examen d'imagerie, par exemple une échocardiographie transthoracique bidimensionnelle. Nous exposons le cas d'une patiente présentant un diverticule ventriculaire droit isolé et un anévrisme ventriculaire gauche qui ont été décelés lors d'une échocardiographie transthoracique en contexte d'embolie pulmonaire. Nous expliquons comment faire la distinction entre un anévrisme et un diverticule en se fondant sur le déplacement de la paroi à l'échocardiographie, ainsi que les complications qui peuvent découler de ces deux anomalies.

Streptococcus anginosus purulent pericarditis with cardiac tamponade after coronary artery bypass surgery.

Purulent pericarditis caused by Streptococcus anginosus is extremely rare. A 66-year-old man underwent elective coronary artery bypass surgery. This was complicated by sternal wound dehiscence with drainage. Subsequently, he developed fever, progressive dyspnoea and presyncope. Echocardiography showed a large pericardial effusion with evidence of tamponade. He underwent emergent pericardiocentesis. The pericardial fluid culture grew S. anginosus He was treated with 4 weeks of intravenous ceftriaxone with complete clinical recovery. The source of infection was most likely the sternal wound which was overlooked during debridement and rewiring surgery.

A leaking spontaneous coronary artery pseudoaneurysm.

A 78-year-old man presented with chest pain and ST segment elevation. Coronary angiography showed no significant coronary artery disease. A saccular pocket of contrast material was found outside of the distal right posterior descending coronary artery consistent with a pseudoaneurysm. Echocardiography showed a pocket of pericardial fluid behind the left atrium concerning for a hemopericardium. The pseudoaneurysm was treated urgently with two coils successfully deployed to obtain complete exclusion of the pseudoaneurysm sac and occlusion of the distal portion of the posterior descending coronary artery.

Eustachian valve, interatrial shunt, and paradoxical embolism.

Randomized clinical trials demonstrate that percutaneous closure of the patent oval foramen is a safe and effective treatment for secondary prevention of cryptogenic stroke in selected patients. The Eustachian valve is generally considered an incidental finding without any significant pathophysiological consequences in adults. However, a persistent Eustachian valve, particularly a prominent one, is significantly more prevalent in patients with patent oval foramen and cryptogenic stroke, and is associated with adverse outcomes following percutaneous closure. Therefore, the Eustachian valve may not be an incidental finding or an innocent bystander. By directing the blood flow from the inferior caval vein to the interatrial septum, the persistence of a Eustachian valve may prevent spontaneous closure of the oval foramen, and predispose to paradoxical embolism during adulthood. The Eustachian valve should be considered an adjunctive risk factor for paradoxical embolism in patients with patent oval foramen. Furthermore, the Eustachian valve has been included in several risk prediction models to identify patients at the highest risk of paradoxical embolism and such patients may benefit the most from an intervention.

Three-dimensional echocardiography assessment of carcinoid valvular heart disease: Images of each and all.

A 54-year-old male was found to have neuroendocrine carcinoma with hepatic metastasis. Two-dimensional (2D) transthoracic echocardiography (TTE) demonstrated dilated right ventricle and right atrium, and severe tricuspid and pulmonary regurgitation. Three-dimensional (3D) TTE en-face views showed thickened, retracted, and fixed tricuspid valve and pulmonic valve which remained widely open throughout the cardiac cycle. 3D TTE, particularly en-face views, demonstrates incremental value over 2D TTE by providing precise valvular anatomic details comparable to surgical findings. 3D TTE also offers a unique opportunity to assess all four valves simultaneously with en-face views to delineate their relationships with surrounding structures.

[Intervention effects of oral active AdipoRon on liver oxidative stress in type 2 diabetic mice].

OBJECTIVE: To explore the intervention effects of oral active AdipoRon on liver oxidative stress in type 2 diabetic mice, which provides basic data for clinical application. METHODS: Thirty-two healthy male C57BL/6 mice were divided into 4 groups:normal group (NC, n=8), diabetes mellitus group (DM, n=8), high dose AdipoRon treatment group (DM + H, n=8) and low dose AdipoRon treatment group (DM + L, n=8). Following six weeks high fat feed, mice of DM, DM + H and DM + L were intraperitoneally injected with 40 mg/kg streptozocin (STZ), leading to type 2 diabetes. Afterwards, DM + H group and DM + L group were continuously treated with high dose and low doses of oral AdipoRon respectively for 10 days, following which, related biochemical indicators were detected. Western blot method was used to detect the p-IRS-1 protein expression in liver tissue and RT-PCR method to detect PDX-1 mRNA expression in the pancreas. RESULTS: The blood glucose of DM group was obviously higher than that of NC group (P < 0.05). Compared to that of DM group, blood glucose of DM + H group as well as DM + L group was significantly lower. Activity of superoxide dismutase (SOD), catalase (CAT) in liver tissue of DM mice was significantly lower than that of NC group (P < 0.05); activity of malondialdehyde (MDA) and nitric oxide synthase (NOS) in DM group significantly higher than that of NC group (P < 0.05); activity of SOD and CAT in DM + L group and DM + H group obviously higher than DM group (P < 0.05); activity of MDA and NOS in DM + L group and DM + H group significantly lower than DM group (P < 0.05). And the p-IRS-1 protein expression in liver tissue and PDX-1 mRNA level in pancreas increased significantly (P < 0.05). CONCLUSIONS: Oral active Adi-poRon which reduced the blood glucose levels of mice had a certain intervention effect on liver tissue oxidative stress in type 2 diabetes mice.

Left Ventricular Dyssynchrony by Three-Dimensional Echocardiography: Current Understanding and Potential Future Clinical Applications.

Left ventricular mechanical dyssynchrony is an important prognostic factor for patients with symptomatic systolic heart failure and has emerged as a therapeutic target for cardiac resynchronization therapy (CRT). However, approximately one-third of patients fail to improve after CRT based on current guideline recommendations and electrocardiographic criteria. Two-dimensional echocardiography and tissue Doppler-based techniques have shown variable results in assessment of left ventricular (LV) dyssynchrony and have limited value in clinical practice. Three-dimensional echocardiography (3DE) is an appealing novel imaging modality that has been recently used in quantitative evaluation of global and regional LV function. There is accumulating evidence that 3DE measurement of LV systolic dyssynchrony index may potentially play a role in predicting the short- and long-term response to CRT and further improve patient selection for CRT. New developments in 3DE speckle tracking technique and strain analysis may further improve the accuracy of LV mechanical dyssynchrony assessment in this population. In addition, recent studies suggest that mechanical dyssynchrony is present in patients with LV hypertrophy and diastolic heart failure. Three-dimensional echocardiographic assessment of dyssynchrony may aid in diagnosis and in predicting long-term outcome in these patients. We will summarize current understanding of 3DE techniques and parameters in assessment of LV mechanical dyssynchrony in the population of patients with systolic heart failure, LV hypertrophy, and diastolic heart failure. A number of the novel 3DE techniques described in this review are early in their stage of development, and they will continue to evolve and need further testing in large multicenter studies.

Multimodality imaging and transcatheter coil embolization of an iatrogenic subclavian artery-internal jugular vein fistula.

A 69-year-old man was found to have a loud continuous bruit in the neck. Duplex carotid ultrasound showed high-velocity turbulent flow in the dilated and pulsatile right internal jugular vein. Computed tomography angiogram demonstrated markedly enlarged right internal jugular vein with a posteriorly located arteriovenous communication. Invasive angiography revealed an arteriovenous fistula originating from the right subclavian artery draining into the dilated and tortuous right internal jugular vein. An endovascular coil was successfully deployed in the fistula tract. Subclavian artery-internal jugular vein fistula is rare. Our case is most likely iatrogenic towing to previous central venous cannulation during coronary bypass grafting. The anatomic challenge of this fistula, being located in the thoracic outlet, makes endovascular repair particularly favourable.

The left bundle-branch block puzzle in the 2013 ST-elevation myocardial infarction guideline: from falsely declaring emergency to denying reperfusion in a high-risk population. Are the Sgarbossa Criteria ready for prime time?

Prompt and accurate identification of ST-elevation myocardial infarction (STEMI) in the presence of left bundle-branch block (LBBB) remains difficult. The 2004 STEMI guideline recommended emergent reperfusion therapy to patients with suspected ischemia and new or presumably new LBBB. These recommendations have led to frequent false catheterization laboratory activation and inappropriate fibrinolytic therapy because most patients with suspected ischemia and new or presumably new LBBB do not have acute coronary artery occlusion on angiography. The new 2013 STEMI guideline makes a drastic change by removing previous recommendations. Therefore, patients with suspected ischemia and new or presumably new LBBB would no longer be treated as STEMI equivalent. The new guideline fails to recognize that some patients with suspected ischemia and LBBB do have STEMI, and denying reperfusion therapy could be fatal. The Sgarbossa electrocardiography criteria are the most validated tool to aid in the diagnosis of STEMI in the presence of LBBB. A Sgarbossa score of ≥3 has a superb specificity (98%) and positive predictive value for acute myocardial infarction and angiography-confirmed acute coronary occlusion. Thus, we propose a diagnosis and triage algorithm incorporating the Sgarbossa criteria to quickly and accurately identify, among patients presenting with chest pain and new or presumably new LBBB, those with acute coronary artery occlusion. This is a high-risk population in which reperfusion therapy would be denied by the 2013 STEMI guideline. Our algorithm will also significantly reduce false catheterization laboratory activation and inappropriate fibrinolytic therapy, the inevitable consequence of the 2004 STEMI guideline.

Coronary artery disease in patients with chronic kidney disease: a clinical update.

Chronic kidney disease (CKD) is an independent risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of morbidity and mortality in patients with CKD. The outcomes of CAD are poorer in patients with CKD. In addition to traditional risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, coronary artery calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis. A number of uremia-related biomarkers are identified as predictors of cardiac outcomes in CKD patients. The symptoms of CAD may not be typical in patients with CKD. Both dobutamine stress echocardiography and radionuclide myocardial perfusion imaging have moderate sensitivity and specificity in detecting obstructive CAD in CKD patients. Invasive coronary angiography carries a risk of contrast nephropathy in patients with advanced CKD. It should be reserved for those patients with a high risk for CAD and those who would benefit from revascularization. Guideline-recommended therapies are, in general, underutilized in renal patients. Medical therapy should be considered the initial strategy for clinically stable CAD. The effects of statins in patients with advanced CKD have been neutral despite a lipid-lowering effect. Compared to non-CKD population, percutaneous coronary intervention (PCI) is associated with higher procedure complications, restenosis, and future cardiac events even in the drug-eluting stent era in patients with CKD. Compared with PCI, coronary artery bypass grafting (CABG) reduces repeat revascularizations but is associated with significant perioperative morbidity and mortality. Screening for CAD is an important part of preoperative evaluation for kidney transplant candidates.

Three-dimensional echocardiography in evaluation of left ventricular indices.

Accurate determination of left ventricular mass, volume, ejection fraction, and wall motion is important for clinical decision making. Currently, M-mode and two-dimensional echocardiography (2DE) have been routinely used for this purpose. Although these 1D or 2D modalities provide excellent diagnostic and prognostic information, they have a number of technical limitations including the time required to perform the procedure and operator-dependent image acquisitions. In addition, they are inherently limited by geometric assumption of three-dimensional (3D) left ventricular structures based on 2D slices. With the improvement in transducer technology and software development, 3D echocardiography (3DE) has become widely available. Left ventricular quantitation by 3DE has been demonstrated to be accurate by multiple studies that compared 3DE with reference techniques. In addition, 3DE measurements were found to be more reproducible and less variable than 2DE. Real time 3DE imaging has potential advantages in stress echocardiography including rapid acquisition, unlimited number of planes, avoidance of foreshortening, and precise segment matching. This is a major step forward in our diagnostic armamentarium for the evaluation of ischemia. In this review, we summarized the current evidence of 3DE for left ventricular evaluation.

Three-dimensional echocardiography in valvular heart disease.

Two-dimensional echocardiography (2DE) with color Doppler has been the standard tool for assessing valvular heart disease. However, this requires conceptualizing three-dimensional (3D) valvular anatomy from individual 2D slices, which is inadequate for complex valvular abnormalities. Similarly, Doppler-based methods are inherently limited by several assumptions and are influenced by hemodynamics and concomitant valvular disease. 3DE has improved both morphological and functional assessment of valvular heart disease. It provides additional morphological information, which leads to better understanding of the mechanism of valvular dysfunction and surgical planning. 3D planimetry has proven to be accurate in the evaluation of valvular stenosis. This direct assessment eliminates measurement errors and could potentially serve as new gold standard. The continuity equation for aortic stenosis can be simplified by directly measuring left ventricular outflow tract area and stroke volume. In patients with valvular regurgitation, vena contracta area can be directly measured by using 3D color Doppler which is more accurate than the standard 2D methods. By applying hemi-elliptical formula or directly measuring isovelocity surface area, 3DE has significantly improved the accuracy in regurgitant severity assessment. This is particularly useful in patients with eccentric jets. 3DE has an advantage over 2DE in assessment of tricuspid valve due to its complex geometry. Direct planimetry of orifice area in tricuspid stenosis, or vena contracta area in tricuspid regurgitation are promising although validation studies are needed before they can be applied for clinical decision making. 3DE has not been widely studied in pulmonic valve disease but preliminary data indicate that it is feasible.

The use of echocardiography in Wolff-Parkinson-White syndrome.

Endocardial mapping and radiofrequency catheter ablation are well established modalities for the diagnosis and treatment of patients with Wolff-Parkinson-White (WPW) syndrome associated with tachyarrhythmias. However, the electrophysiologic techniques are invasive, require radiation exposure, and lack spatial resolution of cardiac structures. A variety of echocardiographic techniques have been investigated as a non-invasive alternative for accessory pathway localization. Conventional M-mode echocardiography can detect the fine premature wall motion abnormalities associated with WPW syndrome. However, it is unable to identify the exact site of accessory pathway with sufficient accuracy. 2D, 2D-guided M-mode, and 2D phase analysis techniques are limited by image quality and endocardial border definition. Various modalities of tissue Doppler echocardiography significantly increase the accuracy of left-sided accessory pathway localization to 80-90% even in patients with poor acoustic window. However, right-sided pathways remain a diagnostic challenge. Strain echocardiography by speckle tracking has recently been evaluated and appears promising. Different cardiac abnormalities have been detected by echocardiography in WPW patients. Patients with WPW syndrome and tachyarrhythmias have impaired systolic and diastolic function which improves after radiofrequency ablation. Echocardiography is useful in identifying patient with accessory pathway-associated left ventricular dyssynchrony and dysfunction who may benefit from ablation therapy. Transesophageal and intracardiac echocardiography have been used to guide ablation procedure. Ablation-related complications detected by routine echocardiography are infrequent, rarely clinically relevant, and of limited value.

Very Late Development of Coronary Artery Aneurysm with Total Occlusion following Sirolimus-Eluting Stent Implantation.

A 41-year-old African American woman presented with chest pain and was found to have non-ST segment elevation myocardial infarction with a peak cardiac troponin I of 28.5. Elective cardiac catheterization revealed a 70% ostial left anterior descending (LAD) artery stenosis. The patient underwent percutaneous coronary intervention and a sirolimus-eluting stent (Cypher, Miami, FL, 3.5 × 8 mm) was successfully deployed. Three years after stent implantation, the patient presented with recurrent angina. Repeat coronary angiography revealed a large aneurysm involving the proximal portion of the stent with a total occlusion at the mid to distal portion of the stent with collaterals to LAD from left circumflex artery. The patient underwent coronary artery bypass surgery with left internal mammary artery graft to LAD and ligation of LAD at its origin proximal to the aneurysm.

Use of impella ventricular assist device in patients with severe coronary artery disease presenting with cardiac arrest.

Impella (Abiomed, Danvers, MA) is a percutaneously inserted ventricular assist device (VAD). It has been increasingly used in patients with severe heart failure, cardiogenic shock, and high-risk percutaneous intervention (PCI). However, the use and efficacy of Impella in patients with severe coronary artery disease (CAD) presenting with cardiac arrest has rarely been reported.The objective of this study is to report our center experience in using Impella VAD in CAD patients presenting with cardiac arrest. From December 2010 to March 2011, three patients with severe CAD presented to our center with cardiac arrest underwent PCI with Impella support. We reported three cases of severe CAD presenting with cardiac arrest successfully treated with PCI and Impella support. Our experience demonstrated that Impella VAD may play an adjunctive role in obtaining hemodynamic stability in these high-risk patients undergoing PCI. One of the patients was supported to left VAD implantation, and the other two had excellent neurological and functional recovery. Our reports suggest an important role of Impella in cardiac arrest population. Earlier Impella implantation after cardiac arrest might provide cardiac support and tissue perfusion until recovery or high-risk PCI.

Molecular characterization and antimicrobial susceptibility of nasal Staphylococcus aureus isolates from a Chinese medical college campus.

Staphylococcus aureus colonization and infection occur more commonly among persons living or working in crowded conditions, but characterization of S. aureus colonization within medical communities in China is lacking. A total of 144 (15.4%, 144/935) S. aureus isolates, including 28 (3.0%, 28/935) MRSA isolates, were recovered from the nares of 935 healthy human volunteers residing on a Chinese medical college campus. All S. aureus isolates were susceptible to vancomycin, quinupristin/dalfopristin and linezolid but the majority were resistant to penicillin (96.5%), ampicillin/sulbactam (83.3%) and trimethoprim/sulfamethoxazole (93.1%). 82%, (23/28) of the MRSA isolates and 66% (77/116) of the MSSA isolates were resistant to multiple antibiotics, and 3 MRSA isolates were resistant to mupirocin--an agent commonly used for nasal decolonization. 16 different sequence types (STs), as well as SCCmec genes II, III, IVd, and V, were represented among MRSA isolates. We also identified, for the first time, two novel STs (ST1778 and ST1779) and 5 novel spa types for MRSA. MRSA isolates were distributed in different sporadic clones, and ST59-MRSA-VId- t437 was found within 3 MRSA isolates. Moreover, one isolate with multidrug resistance belonging to ST398-MRSA-V- t571 associated with animal infections was identified, and 3 isolates distributed in three different clones harbored PVL genes. Collectively, these data indicate a high prevalence of nasal MRSA carriage and molecular heterogeneity of S. aureus isolates among persons residing on a Chinese medical college campus. Identification of epidemic MRSA clones associated with community infection supports the need for more effective infection control measures to reduce nasal carriage and prevent dissemination of MRSA to hospitalized patients and health care workers in this community.

Cardiac allograft vasculopathy: advances in diagnosis.

Cardiac allograft vasculopathy (CAV), characterized by diffuse intimal thickening and luminal narrowing in the arteries of the allograft, is the leading cause of morbidity and mortality in cardiac transplant recipients. Many transplant centers perform routine annual surveillance coronary angiography. However, angiography can underdiagnose or miss CAV due to its diffuse nature. Intravascular ultrasound (IVUS) is more sensitive than angiography. IVUS provides not only accurate information on lumen size, but also quantification of intimal thickening, vessel wall morphology, and composition. IVUS has evolved as a valuable adjunct to angiography and the optimal diagnostic tool for early detection. Noninvasive testing such as dobutamine stress echocardiography and nuclear stress test have shown considerable accuracy in diagnosing significant CAV. Computed tomographic imaging and cardiac magnetic resonance imaging are promising new modalities but require further study. This article reviews the diagnostic methods that are currently available.

A preoperative echocardiographic predictive model for assessment of cardiovascular outcome after renal transplantation.

OBJECTIVE: Major adverse cardiac events (MACE) frequently determine the outcome of renal transplantation (RT). Stress testing is advocated for preoperative risk assessment, but limited information is available on the prognostic value of these tests. We aimed to retrospectively assess the value of preoperative dobutamine stress echocardiography (DSE) in predicting MACE in patients undergoing RT. METHODS: A total of 185 patients (age 56 +/- 11 years, 64% were men, creatinine level of 7.3 +/- 2.9 mg/d, 27% were smokers, 86% had hypertension, 54% had diabetes, 57% were dyslipidemic) with end-stage renal disease (ESRD) underwent DSE before RT. A standard DSE protocol was used with the administration of 5-50 mug/kg/min incremental doses in 3-minute intervals and up to 1 mg of atropine if needed to reach prespecified end points. RESULTS: Regional left ventricular wall motion abnormality (WMA) at rest (fixed), with stress (inducible), or both were present in 54, 35, and 18 patients, respectively. In 38 patients who underwent coronary angiography, the sensitivity, specificity, and positive and negative predictive values of inducible WMA for predicting angiographic coronary artery disease (> or = 70% luminal diameter reduction) were 88%, 62%, 65%, and 87%, respectively. Cox regression analysis identified the presence of combined fixed and inducible WMA (ie, resting WMA that did not change during DSE, accompanied by new WMA evident during DSE; hazard ratio [HR] 5.6, P = .012), left atrial enlargement (HR 4.2, P = .002), and aortic valve sclerosis (HR 3.9, P = .013) as independent predictors of 48-month MACE (cardiac death, nonfatal acute myocardial infarction, and coronary revascularization after RT). Patients with all 3 predictors had a 48-month MACE of 60% compared with 5% in those with none (P = .007). Compared with those without WMA, patients with both fixed and inducible WMA had a higher rate of MACE at 48 months (7% vs 33%, P = .004). CONCLUSION: In RT candidates, DSE can effectively identify those at low and high risk of MACE.