Dose-Related Hemodynamic and Electrocardiographic Effects of the Calcium Promoter BAY y 5959 in the Presence or Absence of Congestive Heart Failure

Objectives. The aim of this study was to assess the cardiovascular effects of BAY y 5959, a calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure.

Background. There is still a clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as a new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes.

Methods. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasma samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 μg/kg body weight per min.

Results. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasma levels of 100 μg/liter). BAY y 5959 also induced mild but statistically significant bradycardia and significantly decreased end-systolic volume while producing a leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 μg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 μg/kg per min (+23%, p < 0.05). However, at a dose of 4.5 μg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses.

Conclusions. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response— combining bradycardia, reduced preload and improved cardiac output—appeared to be achieved at a dose of 2.0 μg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.     

The effects of shallow versus deep endotracheal suctioning on the cytological components of respiratory aspirates in high-risk infants

BACKGROUND: The harmful effects of mechanical ventilation and suctioning are compounded if endotracheal suctioning (ETS) is inappropriately performed. Deep ETS involves catheter insertion into the endotracheal tube until resistance is met. Shallow ETS may be beneficial in lessening mechanical irritation to the first bronchial layers. However, clinical observation reveals wide variation in the length of the suction catheter for ETS in high-risk infants. OBJECTIVE: The study was conducted to examine the effects of deep and shallow ETS on the cytological components of respiratory aspirates from high-risk infants. METHODS: A cross-over experimental study was performed in 22 high-risk infants with a mean birth weight of 2200 g. Whether deep or shallow ETS was conducted first was determined randomly. The numbers of (1). columnar cells [CC - ciliated (CCC) and nonciliated (NCC)], (2). fresh clustered columnar cells (CLCC), and (3). Curschmann's spirals (CS), a mucus cast residing inside the lower terminal airways, in the respiratory aspirates were compared between the two ETS protocols. RESULTS: No statistical differences were found in the quantities of CC, CLCC and NCC between shallow and deep ETS. However, greater quantities of CLCC were observed in the deep ETS aspirates than in the shallow ETS aspirates. CONCLUSIONS: Detachment of larger amounts of clustered columnar cells from the respiratory epithelium without the guarantee that lung secretions from the lower airways will be removed questions the justification of deep ETS in high-risk infants.     

Formation of nanopores in DiynePC–DPPC complex lipid bilayers triggered by on-demand photo-polymerization

Vesicles have unique characteristics that enable the release of drugs as well as encapsulation while maintaining biocompatibility. A photo-polymerizable liposome composed of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (23:2 DiynePC) has been investigated as vehicles for triggered delivery of drugs to cells. In this study, we confirmed for the first time that supported lipid bilayers (SLBs) prepared with a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/DiynePC mixture generated pores ca. 100–300 nm in size on the membrane after UV polymerization. This direct observation was done by analyzing the SLBs formed with the DPPC/DiynePC mixture by employing atomic force microscopy (AFM) in a liquid environment. However, photo-polymerization did not occur in the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/DiynePC mixed bilayer and pores were not formed. A theoretical study was performed to explore the phase behavior of the lipid mixtures. A coarse-grained model of DiynePC was developed that is comparable with the Martini force field; the parameters were validated against atomistic simulations. Transition from fluidic to gel phase was observed only when DiynePC was mixed with DPPC, whereas the DOPC mixture remained fluidic over the entire domain. This implies a correlation between the formation of DiynePC-rich gel phase domains and the generation of pores after polymerization. The size of the pores were found to be controlled by the amount of polymerizable lipid which results in higher release rate of encapsulated calcein from the vesicles with larger pores.

Nanopores generated upon photo-polymerization of the lipid membrane containing DiynePC were identified and their size was controllable.     

Characteristics of K+ Outward Currents in the Cochlear Outer Hair Cells of Circling Mice within the First Postnatal Week

K⁺ outward currents in the outer hair cells (OHCs) of circling mice (homozygous (cir/cir) mice), an animal model for human deafness (DFNB6 type), were investigated using a whole cell patch clamp technique. Littermate heterozygous (+/cir) mice of the same age (postnatal day (P) 0 -P6) were used as controls. Similar slow rising K⁺ currents were observed in both genotypes, but their biophysical and pharmacological properties were quite different. The values of V_half for activation were significantly different in the heterozygous (+/cir) and homozygous (cir/cir) mice (-8.1±2.2 mV, heterozygous (+/cir) mice (n=7) and -17.2±4.2 mV, homozygous (cir/cir) mice (n=5)). The inactivation curve was expressed by a single first order Boltzmann equation in the homozygous (cir/cir) mice, while it was expressed by a sum of two first order Boltzmann equations in the heterozygous (+/cir) mice. The K⁺ current of homozygous (cir/cir) mice was more sensitive to TEA in the 1 to 10 mM range, while the 4-AP sensitivities were not different between the two genotypes. Removal of external Ca²⁺ did not affect the K⁺ currents in either genotype, indicating that the higher sensitivity of K⁺ current to TEA in the homozygous (cir/cir) mice was not due to an early expression of Ca²⁺ activated K⁺ channels. Our results suggest that the K⁺ outward current of developing homozygous (cir/cir) mice OHCs is different in both biophysical and pharmacological aspects than that of heterozygous (+/cir) mice.     

BVAS version 3 and BVAS/GPA: standing on the same line?

Clinical Rheumatology - Birmingham vasculitis activity score (BVAS) version 3 (BVAS 3.0) and BVAS/granulomatosis with polyangiitis (BVAS/GPA) are used as indicators of disease activity in...