Novel series of non-glycerol-based cationic transfection lipids for use in liposomal gene delivery.

A novel series of nontoxic and non-glycerol-based simple monocationic transfection lipids containing one or two hydroxyethyl groups directly linked to the positively charged nitrogen atom were synthesized. The in vitro transfection efficiencies of these new liposomal gene delivery reagents were better than that of lipofectamine, a widely used transfection agent in cationic lipid-mediated gene transfer. The most efficient transfection formulation was observed to be a 1:1:0.3 mol ratio of DHDEAB (N, N-di-n-hexadecyl-N,N-dihydroxyethylammonium bromide):cholesterol:HDEAB (N-n-hexadecyl-N,N-dihydroxyethylammonium bromide) using a DHDEAB-to-DNA charge ratio (+/-) of 0.3:1. Observation of good transfection at charge ratios lower than 1 suggests that the amphiphile-DNA complex may have net negative charge. Our results reemphasize the important point that in cationic lipid-mediated gene delivery, the overall charge of the lipid-DNA complex need not always be positive. In addition, our transfection results also imply that favorable hydrogen-bonding interactions between the lipid headgroups and the cell surface of biological membranes may have some role for improving the transfection efficiency in cationic lipid-mediated gene delivery.     

Neutrophil extracellular traps and thrombosis in COVID-19

Journal of Thrombosis and Thrombolysis - Studies of patients with COVID-19 have demonstrated markedly dysregulated coagulation and a high risk of morbid arterial and venous thrombotic events....     

Validation of the GRACE score for prognosis in Indian patients with acute coronary syndromes

AimTo validate the global registry of acute coronary events (GRACE) score in acute coronary syndromes (ACS) patients and study its angiographic correlation.Methods and resultsTwo-hundred and thirty-five ACS patients were studied for the combined endpoint of all-cause in-hospital mortality and non-fatal infarction/reinfarction. We tested the predictive accuracy of the composite GRACE score using the receiver operating characteristics (ROC) curve.Lower systolic blood pressure (SBP) (odds ratio [OR] 7.93, P=0.005), ST-segment deviation (OR 7.79, P=0.02) and cardiac biomarker positivity (OR > 6.52, P=0.01) were significantly associated with events. Serum creatinine > 1.4 mg/dL showed a trend towards statistical significance (OR 4.14, P=0.05), whereas age > 50 years (OR 3.62, P=not significant [NS]) and Killips class 4 (OR 2.71, P=NS) showed good association. The best value for predicting events was a GRACE score of > 217 and these patients were more likely to have double/triple vessel disease (P = 0.0009). The C statistic for the GRACE score was 0.75.ConclusionHigher GRACE score predicts in-hospital events and more severe angiographic coronary artery disease (CAD).     

Hemodynamic,Autonomic, and Vascular Effects of Exposure to Coarse Particulate Matter Air Pollution from a Rural Location

Background: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown.Objectives: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses.Methods: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 μg/m³) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures.Results: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures.Conclusions: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events.Citation: Brook RD, Bard RL, Morishita M, Dvonch JT, Wang L, Yang HY, Spino C, Mukherjee B, Kaplan MJ, Yalavarthi S, Oral EA, Ajluni N, Sun Q, Brook JR, Harkema J, Rajagopalan S. 2014. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environ Health Perspect 122:624–630; http://dx.doi.org/10.1289/ehp.1306595     

Architecture of the left ventricle: insights for optimal surgical ventricular restoration

The normal left ventricular shape has been defined as prolate ellipsoid. This shape is an adaptation to evolution. A knowledge of its unique macro and micro architecture forms the cornerstone in the understanding of its complex function. The left ventricle has a unique architecture with three different myofiber orientations, the longitudinal, circumferential and oblique fibers. The oblique orientation of fibers is essential for effective clockwise and anticlockwise torsional movements during systole and diastole, for optimal ventricular ejection and filling. The orientation and fiber angle decide the shape of the ventricle. An ellipsoid shape is vital for optimal function. Pathological disease states such as ischemic heart disease, valvular heart disease and cardiomyopathies cause a loss of obliquity of the myofibers. The myofibers become more horizontal resulting in ventricular dilatation and increased sphericity. The change from ellipsoid to globular shape with disease heralds the onset of left ventricular dysfunction and initiates the cascade of heart failure. Several strategies have been successful in reverting ventricular dilatation and sphericity to a more ellipsoid geometry. Pharmacological therapies like beta blockade and angiotensin converting enzyme inhibition have proven beneficial in early stages of heart failure with pathological remodeling. However, these agents in isolation are limited in reversing pathological remodeling in advanced heart failure. In some cases of advanced heart failure due to postinfarction left ventricular aneurysms, ventricular volume reduction with restoration surgeries have a role in restoring ventricular geometry with beneficial clinical outcomes. Surgical ventricular restoration has progressively evolved from the 1950s. Initially, aneurysmal resection and linear repair was done. This was gradually replaced by endoventricular patch plasty, which had better results. The resulting left ventricle was smaller in size but still continued to have a spherical configuration. Exclusion of the infarct area with a smaller longitudinal patch results in realignment of the non-diseased ventricular fibers with a resulting ellipsoid shape. This ellipsoid shape ensures clinical benefits. The geometry of the endoventricular patch thus holds the key to optimal ventricular shape in these patients. The technique to optimally restore a diseased ventricle to normal continues to evolve. This requires insights into the normal architecture and function, and the pathophysiologic effects of disease.     

A phase I trial of 5-fluorouracil, folinic acid, and alpha-2a-interferon in patients with metastatic colorectal carcinoma.

The mechanisms of biochemical modulation of 5-fluorouracil (5-FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha-2a-interferon (rHuIFN-alpha 2a) and 5-FU. Therefore, a Phase I trial of these three agents 5-FU, FA, and rHuIFN-alpha 2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN-alpha 2a or 5-FU. Fifty-five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5-FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN-alpha 2a 4.0 x 10(6) U/m2/d subcutaneously on days 1 to 5. The dose-limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing.     

Subclinical endophthalmitis following a rooster attack

Ocular injury resulting from rooster attacks is rarely reported in the literature. Sadly, the target of these attacks is most often children younger than 3 years old, whose naiveté of the aggressive, territorial behavior of birds can place them at risk. Acute sequelae of these attacks can result in a lifetime of visual impairment. The possibility of a subacute or occult infection is an unusual occurrence that must always be considered. In an effort to prevent future attacks and ocular casualties, we present a case of a 12-month-old boy who suffered an open globe following a rooster attack. The open globe was emergently repaired. One week later, a white cataract was noticed on examination in the absence of systemic or ocular signs of inflammation. Traumatic endophthalmitis and lenticular abscess were suspected during examination under anesthesia. Vitrectomy, lensectomy, and injection of intravitreal antibiotics were performed. Culture of lenticular and vitreous aspirates grew alpha-streptococcus. Alpha-streptococcal endophthalmitis can result from ocular injuries caused by rooster pecking. The infection may present insidiously and without typical ocular or systemic symptoms or signs. Management is challenging and may require surgery.