Influence of nanocrystal size on the in vivo absorption kinetics of caffeine after topical application.

The absorption of topically applied substances is challenging due to the effective skin barrier. Encapsulation of substances into nanoparticles was expected to be promising to increase the bioavailability of topically applied products. Since nanoparticles cannot traverse the intact skin barrier, but penetrate into the hair follicles, they could be used to deliver substances via hair follicles, where the active is released and can translocate independently transfollicularly into the viable epidermis. In the present in vivo study, this effect was investigated for caffeine. Caffeine nanocrystals of two sizes, 206 nm and 694 nm, with equal amounts of caffeine were used to study caffeine serum concentration kinetics after topical application on 5 human volunteers. The study demonstrated that at early time points, the smaller nanocrystals were more effective in increasing the bioavailability of caffeine, whereas after 20 min, the serum concentration of caffeine was higher when caffeine was applied by larger nanocrystals. Caffeine was still detectable after 5 days. The area under the curve could be increased by 82% when the 694 nm nanocrystals were applied. Especially larger sized nanocrystals seem to be a promising type of nanoparticulate preparation to increase the bioavailability of topically applied drugs via the transfollicular penetration pathway.

Pericardial complications and postcardiac injury syndrome after cardiovascular implantable electronic device placement : A meta-analysis and systematic review.

BACKGROUND: Postcardiac injury syndrome (PCIS) is an emerging condition including pericarditis with or without pericardial effusion after an injury to cardiac tissue. Data are lacking on its incidence and clinical predictors after cardiovascular implantable electronic device (CIED) placement. We therefore performed this meta-analysis to determine the incidence of PCIS. METHODS: Medline, Embase, and Cochrane CENTRAL databases were searched according to PRISMA guidelines from February 2007 to February 2017 for studies evaluating pericardial complications subsequent to CIED implantation. Primary outcome was the total number of cases of pericarditis, pericardial effusion, and cardiac tamponade documented. RESULTS: Of 2931 references, 22 articles (enrolling 188,944 patients) were included. Pooled estimates from random-effects analysis showed an overall incidence of 5.82 per 1000 patients (95% confidence interval [CI], 4.33-8.17) at 30 days, and 1.60 per 1000 (95% CI: 0.13-3.07) at 1 year. Advanced age and prior coronary artery bypass graft (CABG) surgery were associated with increased rates of pericardial complications. CONCLUSION: Our analysis revealed that CIED implantations are associated with a low incidence (0.6%) of pericardial complications at 30 days. Patients with advanced age and prior CABG are high-risk patients for pericardial complications.

Sexual Size Dimorphism in the Color Pattern Elements of Two Mimetic Heliconius Butterflies.

Sexual dichromatism and sexual dimorphism of body size are reasonably well studied in butterflies. Sexual size dimorphism of color pattern elements, however, is much less explored. The object of this study is Heliconius, a genus of butterflies well known for the coevolution between mate color preferences and mimicry. Given the sexual role of wing coloration, we investigated the existence of sexual size dimorphism in the wing color elements of a mimetic pair-Heliconius erato phyllis Fabricius and Heliconius besckei Ménétriés-and analyzed the allometric patterns of these traits. Correlation between size of elements in the dorsal and ventral wing surfaces were also estimated. In both species, three out of four elements were larger in males, but the non-dimorphic element was not the same. With regard to the allometric patterns, our most important finding was that smaller males of one species have proportionally larger yellow bars. This is the first study specifically concerning quantitative sexual dimorphism in the coloration of this well-known genus of butterflies and it opens new prospects to investigate sex-related natural selection and sexual selection of color pattern elements.

Independence of restrictive filling pattern and LV ejection fraction with mortality in heart failure: an individual patient meta-analysis.

BACKGROUND: The Doppler echocardiographic restrictive mitral filling pattern (RFP) is an important prognostic indicator in patients with heart failure (HF), but the interaction between RFP, left ventricular ejection fraction (LVEF) and filling pattern remains uncertain. AIMS: To determine whether the RFP is predictive of mortality independently of LVEF in patients with HF. METHODS: Online databases were searched to identify studies assessing the relationship between prognosis and LV filling pattern in patients with HF. Individual patient data from 18 studies (3540 patients) were extracted and collated at the MeRGE Coordinating Centre (The University of Auckland). RESULTS: Overall, RFP was associated with higher all-cause mortality than the non-restrictive filling pattern: hazard ratio 2.42 (95% CI 2.06, 2.83). In multivariable analysis the RFP, LVEF, NYHA class and age were independent predictors of mortality. The prevalence of the RFP was inversely related to LVEF but remained a predictor of mortality even in those patients with preserved LVEF. CONCLUSIONS: The restrictive mitral filling pattern is a powerful predictor of mortality, independent of LVEF and age, in patients with HF. Doppler-derived LV filling patterns are an accessible marker from echocardiography that can readily be incorporated in risk stratification of all patients with HF.

Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction: an individual patient meta-analysis: Meta-Analysis Research Group in Echocardiography acute myocardial infarction.

BACKGROUND: Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved. We undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI. METHODS AND RESULTS: Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20; P<0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF. The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (<39%) and lowest (9%) in patients with the highest LVEF (>53%; P<0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (P=0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome. CONCLUSIONS: Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.

Transesophageal echocardiography in atrial fibrillation. A new paradigm.

Transesophageal echocardiography (TEE) has contributed to our understanding of the patho-physiology of the thromboembolic sequelae of atrial fibrillation. This imaging modality has demonstrated thrombus formation within the left atrial appendage, as well as allowing for assessment of dynamic indices of left atrial appendage function. Studies using TEE have introduced the concept of post conversion "stunning", suggesting an increased milieu for thrombus formation after restoration of sinus rhythm. The detailed assessment of the atrium allowed for by TEE gave rise to the concept of TEE guided cardioversion, bypassing the traditional practice of prolonged anticoagulation prior to cardioversion. The only randomized trial of this practice, the multicenter ACUTE trial, has demonstrated that this strategy is a safe one with less bleeding, and appears to be a strong alternative to the conventional approach. There is some suggestion that TEE may play a role in further risk stratification of patients with chronic atrial fibrillation, but more data is needed on this potential utility of TEE. Treatment strategies for atrial fibrillation are continuing to evolve, and TEE has played a role and will likely continue to play a role in this development.

Respiratory variation of mitral and pulmonary venous Doppler flow velocities in constrictive pericarditis before and after pericardiectomy.

The objective of this study was to determine whether Doppler echocardiography is useful in assessing the effects of pericardiectomy in patients with constrictive pericarditis by studying the postoperative change in the respiratory variation of mitral inflow and pulmonary venous Doppler flows. The study population consisted of 35 cases with surgically proven constrictive pericarditis. Thirty-five patients had preoperative Doppler echocardiography, whereas 4 patients died of non-cardiac causes and 1 patient had a heart transplant before follow-up. Postoperative studies were performed at a mean of 1081 +/- 84 days (range 120-2700 days) after pericardiectomy. The mean (+/- SD) respiratory variation changed after surgery from a baseline value of 17% +/- 14% to 8% +/- 8% for peak mitral E velocity (P <.01); from 25% +/- 18% to 7% +/- 13% (P <.001) for pulmonary venous (PV) peak diastolic flow velocity, and from 21% +/- 13% to 11% +/- 13% (P =.009) for PV peak systolic flow velocity. The 23 patients who became asymptomatic after surgery had a significantly lower mean mitral and PV respiratory variation than the 7 patients who were NYHA class II (4% +/- 4% and 6% +/- 4% vs 21% +/- 6% and 19% +/- 10%, respectively, P <.0001 for both). Pulsed Doppler echocardiographic assessment of respiratory variation is useful for evaluating the outcome of pericardiectomy.

Role of transesophageal echocardiography-guided cardioversion of patients with atrial fibrillation.

Electrical cardioversion of patients with atrial fibrillation (AF) is frequently performed to relieve symptoms and improve cardiac performance. Patients undergoing cardioversion are treated conventionally with therapeutic anticoagulation for three weeks before and four weeks after cardioversion to decrease the risk of thromboembolism. A transesophageal echocardiography (TEE)-guided strategy has been proposed as an alternative that may lower stroke and bleeding events. Patients without atrial cavity thrombus or atrial appendage thrombus by TEE are cardioverted on achievement of therapeutic anticoagulation, whereas cardioversion is delayed in higher risk patients with thrombus. The aim of this review is to discuss the issues and controversies associated with the management of patients with AF undergoing cardioversion. We provide an overview of the TEE-guided and conventional anticoagulation strategies in light of the recently completed Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) clinical trial. The two management strategies comparably lower the patient's embolic risk when the guidelines are properly followed. The TEE-guided strategy with shorter term anticoagulation may lower the incidence of bleeding complications and safely expedite early cardioversion. The inherent advantages and disadvantages of both strategies are presented. The TEE-guided approach with short-term anticoagulation is considered to be a safe and clinically effective alternative to the conventional approach, and it is advocated in patients in whom earlier cardioversion would be clinically beneficial.

Difference in the respiratory variation between pulmonary venous and mitral inflow Doppler velocities in patients with constrictive pericarditis with and without atrial fibrillation.

OBJECTIVES: The goal of this study was to evaluate the difference in the respiratory change from expiration to inspiration (%E) between pulsed Doppler mitral inflow (MV) and pulmonary venous flow (PV) velocities in patients with constrictive pericarditis (CP) and to describe the influence of atrial fibrillation (AF). BACKGROUND: The difference in %E between MV and PV velocities as well as the influence of AF on %E has not been well described. METHODS: Pulsed-wave Doppler transesophageal echocardiography (TEE) was performed with respiratory monitoring in 31 patients with CP and sinus rhythm (SR) and in 10 patients with CP and AF. The MV early (E) and late diastolic (A) velocities and their velocity time integral (VTI) as well as PV systolic (S) and diastolic (D) velocities and their VTI were measured. RESULTS: Regardless of the cardiac rhythm: 1) The MV-E velocity and E-VTI as well as PV-D velocity and D-VTI significantly decreased from expiration to inspiration; 2) the %E in PV-D velocity (27% in SR and 35% in AF) and D-VTI (38% in SR and 45% in AF) was significantly greater than that in MV-E velocity (18% in SR and 15% in AF) and E-VTI (21% in SR and 19% in AF), respectively; 3) the PV S/D and S/D-VTI significantly increased from expiration to inspiration. CONCLUSIONS: A significant respiratory variation was observed in both MV and PV velocities in CP, not only in patients with SR but also in those with AF. Moreover, the %E was greater in the PV velocities than it was in the MV velocities. Evaluation of the %E in the PV velocities using TEE can be a sensitive diagnostic strategy for evaluation of patients with CP, even in patients with AF.

Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.

BACKGROUND: The conventional treatment strategy for patients with atrial fibrillation who are to undergo electrical cardioversion is to prescribe warfarin for anticoagulation for three weeks before cardioversion. It has been proposed that if transesophageal echocardiography reveals no atrial thrombus, cardioversion may be performed safely after only a short period of anticoagulant therapy. METHODS: In a multicenter, randomized, prospective clinical trial, we enrolled 1222 patients with atrial fibrillation of more than two days' duration and assigned them to either treatment guided by the findings on transesophageal echocardiography or conventional treatment. The composite primary end point was cerebrovascular accident, transient ischemic attack, and peripheral embolism within eight weeks. Secondary end points were functional status, successful restoration and maintenance of sinus rhythm, hemorrhage, and death. RESULTS: There was no significant difference between the two treatment groups in the rate of embolic events (five embolic events among 619 patients in the transesophageal-echocardiography group [0.8 percent]) vs. three among 603 patients in the conventional-treatment group [0.5 percent], P=0.50). However, the rate of hemorrhagic events was significantly lower in the transesophageal-echocardiography group (18 events [2.9 percent] vs. 33 events [5.5 percent], P=0.03). Patients in the transesophageal-echocardiography group also had a shorter time to cardioversion (mean [+/-SD], 3.0+/-5.6 vs. 30.6+/-10.6 days, P<0.001) and a greater rate of successful restoration of sinus rhythm (440 patients [71.1 percent] vs. 393 patients [65.2 percent], P=0.03). At eight weeks, there were no significant differences between the two groups in the rates of death or maintenance of sinus rhythm or in functional status. CONCLUSIONS: The use of transesophageal echocardiography to guide the management of atrial fibrillation may be considered a clinically effective alternative strategy to conventional therapy for patients in whom elective cardioversion is planned.

Potential clinical efficacy and cost benefit of a transesophageal echocardiography-guided low-molecular-weight heparin (enoxaparin) approach to antithrombotic therapy in patients undergoing immediate cardioversion from atrial fibrillation.

An alternative clinical management strategy and cost analysis model is presented for patients with atrial fibrillation of >2 days' duration who may benefit from immediate cardioversion with self-administered low-molecular-weight heparin (enoxaparin) as a bridge antithrombotic therapy to warfarin, after a negative transesophageal echo-cardiography (TEE) screening for thrombus. Assuming no difference in stroke or bleeding rates, our cost minimization model shows that the TEE-guided enoxaparin treatment costs are $1353 lower per patient than an intravenous unfractionated heparin approach. Sensitivity analyses for stroke and bleeding reveal that the treatment-cost economic dominance of the TEE-guided enoxaparin approach may be enhanced by an expected improvement in clinical outcome.

Right atrial spontaneous echo contrast and thrombi in atrial fibrillation: a transesophageal echocardiography study.

BACKGROUND: Previous studies have reported the clinical and echocardiographic findings of patients with left atrial spontaneous echo contrast (SEC) and thrombi. We sought to study these characteristics in patients with right atrial SEC and thrombi. METHODS: We reviewed 580 consecutive patients from the ACUTE (Assessment of Cardioversion Using Transesophageal Echocardiography) Registry and found 79 patients (14%, aged 67 +/-13 years, 67 male) with transesophageal echocardiography (TEE) findings of right atrial SEC or thrombi (group 1). This group was compared with a control group of 75 consecutive patients (group 2) (aged 68 +/- 13 years, P = not significant; 49 male, P <.005) from the registry with no TEE findings of SEC or thrombi in the left or right atrium. RESULTS: Atrial fibrillation was present in 60 of 79 group 1 patients (76%). Five right atrial (6%) and 11 left atrial (14%) thrombi were identified. Both left ventricular ejection fraction (39% +/- 16% versus 47% +/- 14%; P =.0005) and presence of right ventricular dysfunction (n = 44 versus 18; P =.0001) differed significantly between groups 1 and 2, respectively. Right atrial area (24 +/- 6 cm(2) versus 22 +/- 6 cm(2); P = .02) was larger in patients in group 1. Left atrial SEC was present in 68 of 79 group 1 patients (86%). Patients with right atrial thrombi and right atrial SEC had a longer duration of arrhythmia (524 +/-812 days versus 147 +/-368 days, P <.05) than patients with right atrial SEC only. CONCLUSIONS: Right atrial SEC has a prevalence of 14% in patients with atrial arrhythmia who undergo TEE-guided cardioversion. Right atrial thrombi are a rare finding and were seen in fewer than 1% (5/580) of patients with atrial arrhythmia. Right atrial thrombi among patients on anticoagulation therapy were not associated with clinically significant pulmonary embolism.

Comparison of new Doppler echocardiographic methods to differentiate constrictive pericardial heart disease and restrictive cardiomyopathy.

This study assesses how the newer modalities of tissue Doppler echocardiography and color M-mode flow propagation compare with respiratory variation of Doppler flow in distinguishing between constrictive pericarditis and restrictive cardiomyopathy. We studied 30 patients referred for further evaluation of diastolic function who had a diagnosis of constrictive pericarditis or restrictive cardiomyopathy established by diagnostic tests, including clinical assessment, magnetic resonance imaging, cardiac catheterization, endomyocardial biopsy, and surgical findings. Nineteen patients had constrictive pericarditis and 11 had restrictive cardiomyopathy. We performed 2-dimensional transesophageal echocardiography combined with pulsed-wave Doppler of the pulmonary veins and mitral inflow with respiratory monitoring, tissue Doppler echocardiography of the lateral mitral annulus, and color M-mode flow propagation of left ventricular filling. Respiratory variation of the mitral inflow peak early (peak E) velocity of > or =10% predicted constrictive pericarditis with 84% sensitivity and 91% specificity and variation in the pulmonary venous peak diastolic (peak D) flow velocity of > or =18% distinguished constriction with 79% sensitivity and 91% specificity. Using tissue Doppler echocardiography, a peak early velocity of longitudinal expansion (peak Ea) of > or =8.0 cm/s differentiated patients with constriction from restriction with 89% sensitivity and 100% specificity. A slope of > or =100 cm/s for the first aliasing contour in color M-mode flow propagation predicted patients with constriction with 74% sensitivity and 91% specificity. Thus, the newer methods of tissue Doppler echocardiography and color M-mode flow propagation are equivalent and complimentary with Doppler respiratory variation in distinguishing between constrictive pericarditis and restrictive cardiomyopathy. The additive role of the new methods needs to be established in difficult cases of constrictive pericarditis where respiratory variation may be absent or decreased.

Left ventricular diastolic dysfunction in lone atrial fibrillation determined by Doppler tissue imaging of mitral annular motion.

In this study, we sought evidence for an underlying atrial or ventricular myopathy in patients with paroxysmal lone atrial fibrillation using standard echocardiographic parameters in addition to Doppler tissue imaging of mitral annular motion. No impairment in atrial contractile function was found, but there was evidence for impaired diastolic function in these patients.

Reversal of the pattern of respiratory variation of Doppler inflow velocities in constrictive pericarditis during mechanical ventilation.

BACKGROUND: Spontaneous inspiration causes a characteristic decrease of the mitral valve (MV) and pulmonary venous (PV) flow velocities obtained by Doppler echocardiography in patients with constrictive pericarditis (CP). This has been explained by the decrement it causes in the intrathoracic pressure. Positive pressure ventilation (PPV) causes an increment of intrathoracic pressure with mechanical inspiration. Therefore the pattern of respiratory variation produced during PPV may differ from that seen during spontaneous breathing. OBJECTIVE: Our goal was to describe the effect of PPV on the pattern and magnitude of respiratory variation of MV and PV flow velocities in CP. METHODS: We performed intraoperative pulsed Doppler transesophageal echocardiography on 15 patients (13 men, mean age 52+/-15 years) with CP after general anesthesia and before sternotomy and pericardial stripping. The peak velocity and time-velocity integral (TVI) of the mitral inflow E and A waves and the PV systolic and diastolic waves were measured at onset of inspiration and expiration for 3 to 6 respiratory cycles. Respiratory phase was monitored with a heat-sensitive nasal thermistor. The percent change in Doppler flow velocities from mechanical inspiration (INS) to mechanical expiration (EXP) was calculated with the formula %change = INS - EXP / INS x 100. RESULTS: The peak velocity of the mitral inflow E wave was significantly higher during mechanical inspiration than expiration (57 +/-14.5 versus 47+/-13.9 cm/s, P<.001). This represented a percent change of 18%+/-7.9% from expiration to inspiration. The mean TVI of the mitral inflow E was also higher during mechanical inspiration than expiration (P = .02). The peak velocity of the PV D wave was higher during mechanical inspiration than expiration (39+/-17.8 versus 28+/-14.7 cm/s, P<.001). This represented a mean percent change of 28%+/-13.8%. The mean value of the TVI for the PV D wave was also significantly greater during mechanical inspiration than expiration (P <.05). CONCLUSIONS: Positive pressure ventilation reverses the pattern of respiratory variation of the MV and PV flow velocities in CP. The percent change in the peak velocities of the MV and PV flows produced by PPV is the same range reported in CP during spontaneous breathing.