Novel forms of ventilation in neonates: Neurally adjusted ventilatory assist and proportional assist ventilation.

Patient-triggered modes of ventilation are currently the standard of practice in the care of term and preterm infants. Maintaining spontaneous breathing during mechanical ventilation promotes earlier weaning and possibly reduces ventilator-induced diaphragmatic dysfunction. A further development of assisted ventilation provides support in proportion to the respiratory effort and enables the patient to have full control of their ventilatory cycle. In this paper we will review the literature on two of these modes of ventilation: neurally adjusted ventilatory assist (NAVA) and proportional assist ventilation (PAV), propose future studies and suggest clinical applications of these modes.

Graphene Nanoplatelet (GNPs) Doped Carbon Nanofiber (CNF) System: Effect of GNPs on the Graphitic Structure of Creep Stress and Non-Creep Stress Stabilized Polyacrylonitrile (PAN).

Improving the graphitic structure in carbon nanofibers (CNFs) is important for exploiting their potential in mechanical, electrical and electrochemical applications. Typically, the synthesis of carbon fibers with a highly graphitized structure demands a high temperature of almost 2500 °C. Furthermore, to achieve an improved graphitic structure, the stabilization of a precursor fiber has to be assisted by the presence of tension in order to enhance the molecular orientation. Keeping this in view, herein we report on the fabrication of graphene nanoplatelets (GNPs) doped carbon nanofibers using electrospinning followed by oxidative stabilization and carbonization. The effect of doping GNPs on the graphitic structure was investigated by carbonizing them at various temperatures (1000 °C, 1200 °C, 1500 °C and 1700 °C). Additionally, a stabilization was achieved with and without constant creep stress (only shrinkage stress) for both pristine and doped precursor nanofibers, which were eventually carbonized at 1700 °C. Our findings reveal that the GNPs doping results in improving the graphitic structure of polyacrylonitrile (PAN). Further, in addition to the templating effect during the nucleation and growth of graphitic crystals, the GNPs encapsulated in the PAN nanofiber matrix act in-situ as micro clamp units performing the anchoring function by preventing the loss of molecular orientation during the stabilization stage, when no external tension is applied to nanofiber mats. The templating effect of the entire graphitization process is reflected by an increased electrical conductivity along the fibers. Simultaneously, the electrical anisotropy is reduced, i.e., the GNPs provide effective pathways with improved conductivity acting like bridges between the nanofibers resulting in an improved conductivity across the fiber direction compared to the pristine PAN system.

Highly anisotropic electric conductivity in PAN-based carbon nanofibers.

In addition to the chemical and physical properties of nanostructures their successful utilization for applications is strongly triggered by economic aspects. Electrospinning of nanowires from solution followed by subsequent annealing steps is a comparably cheap technique to fabricate conductive carbon nanofibers (CNF) made from polyacrylonitrile (PAN) molecules in large quantities. In this work, we investigated the microscopic properties of the CNFs with diameters of 100-300 nm by means of Raman and x-ray photoelectron spectroscopy and correlated these results with transport measurements done with a 4-tip STM. In particular, we investigated the effect of fiber alignment and knot densities, which can be controlled by applying constant creep due to stress during the stabilization process. The comparison of the conductivity obtained from single CNFs revealed further that the fiber crossings within the ensemble structure act as scattering centers and proofs that the transport is along the surfaces of the CNFs.

Bacterial N-formyl Peptides Reduce PMA- and Escherichia coli-Induced Neutrophil Respiratory Burst in Term Neonates and Adults.

Neutrophil migration and respiratory burst are the prerequisite for efficient first line defense against invading microorganisms. However, migration and respiratory burst can be compromised in adults and especially in newborn infants, where sustained neutrophil accumulation, uncontrolled burst and reduced scavenging of ROS might cause inadvertent tissue damage due to uncontrolled inflammation. The aim of this study was to investigate the modulatory effect of the chemoattractants formyl-methionyl-leucyl-phenylalanine (fMLP) and IL-8 on respiratory burst in neutrophils from term newborn infants and adults. Whole blood from the umbilical cord of 17 healthy term newborn infants delivered by caesarean section and from 17 healthy adults as reference was preincubated with fMLP or IL-8 and stimulated with PMA or Escherichia coli bacteria. Respiratory burst was quantified by flow cytometry analysis of dihydrorhodamine 123 fluorescence. fMLP reduced the PMA-induced respiratory burst of neutrophils from newborn infants and adults by 12% and 21%, respectively (P < 0.05). E. coli-induced burst was also reduced by fMLP in neutrophils from newborn infants (10%; P < 0.01) and adults (6%; P < 0.05). No such changes were observed with IL-8. Similar respiratory burst in response to single stimulus with PMA or E. coli was observed in both newborn infants and adults. fMLP reduced PMA- and E. coli-induced respiratory burst of neutrophils in whole blood from term newborn infants as well as in adults. The reduced respiratory burst by fMLP might be a mechanism to reduce the detrimental effects of uncontrolled inflammation during neutrophil migration.

Neutrophil Receptor Response to Bacterial N-formyl Peptides is Similar in Term Newborn Infants and Adults in Contrast to IL-8.

We have previously observed that neutrophils from neonates exhibit different migratory responses to intermediate and end-target chemoattractants compared to adults. The aim of this study was to investigate the effect of the chemoattractants IL-8 (intermediate) and formyl-methionyl-leucyl-phenylalanine (fMLP; end-target) on cell surface receptor expression involved in adhesion, migration and granule release of neutrophils from term newborn infants and adults. Heparinized cord blood from 16 healthy term newborn infants delivered by caesarean section and peripheral blood from 17 healthy adults were incubated with 1 µm IL-8 or 0.1 µm fMLP, previously defined as optimal inducers of neutrophil migration. The leukocytes were labelled with antibodies to cell surface receptors (CD11b, CD15S, CD18, CD35, CD44, CD64, CD65, CD88, CD162, CD181 and CD182). Receptor expression was quantified by flow cytometry analysis. Upregulation of CD11b and downregulation of CD88 and CD182 after stimulation with IL-8 were more pronounced in adults than in neonates (P < 0.05, P < 0.05 and P ≤ 0.001, respectively), whereas fMLP induced changes in receptor expression that were of the same magnitude in neutrophils from neonates as from adults. We observed similar expression of receptors that mediate adhesion, migration, granule activation and phagocytosis induced by fMLP in neutrophils from neonates and adults. In contrast, differences between neonates and adults, induced by IL-8, suggest that the neutrophil response to intermediate chemoattractants might lead to a compromised infectious response in newborn infants.

[Immunogenicity of vaccines against viral hepatitis A and B in the population above 40 years of age -- impact of risk factors]. / Imunogenita vakcín proti virovým hepatitidám A a B u osob starsích 40 let -- vliv rizikových faktoru.

UNLABELLED: The immune reaction following vaccination against viral hepatitis A (HAV) and viral hepatitis B (HBV) can be influenced by a variety of factors. Among the most important are age, gender and body weight. STUDY OBJECTIVE: This prospective randomized study compared immunogenicity of available vaccines against HAV and HBV infections in the population above 40 years of age and the impact of risk factors. MATERIAL AND METHODS: The vaccinated subjects were divided into 3 groups based on the vaccine used. Within each group, the subjects were equally distributed by age, gender and body weight. The vaccine was always applied intramuscularly in the deltoid. Group 1 was given the combined vaccine Twinrix (GSK) against HAV and HBV infections in the left deltoid; group 2 was vaccinated with the Havrix vaccine against HAV (GSK) in the right deltoid and with the Engerix-B vaccine against HBV (GSK) in the left deltoid; group 3 received the Vaqta vaccine against HAV (Sanofi Pasteur) in the right deltoid and the HB VAX PRO against HBV (Sanofi-Pasteur) in the left deltoid. RESULTS: The following anti-HBs seroprotectivity rates: 92%, 80% and 71%, and anti-HAV seropositivity rates: 97%, 99% and 99%, were observed at 1 month after the end of the complete vaccination in groups 1, 2 and 3, respectively. The anti-HBs seroprotectivity rate was statistically significantly higher in group 1. The anti-HAV seropositivity rates were comparable (did not significantly differ) in all three study groups. CONCLUSION: The impact of age was revealed: the immune response decreases with increasing age. The lowest immunogenicity of the vaccines against HAV and HBV infections was observed in subjects above 60 years of age. Males achieved lower geometric mean titres (GMT) of antibodies and lower seroprotectivity rates compared to females. The impact of body weight was also observed, with the obese subjects showing the lowest immune response. The anti-HBs reactivity was significantly influenced by the vaccine used. The combined vaccine against HAV and HBV infections (Twinrix) induced higher anti-HBs seroprotectivity and comparable anti-HAV seropositivity when compared with the other monovalent study vaccines in the population above 40 years of age.

Biologically active quassinoids and their chemistry: potential leads for drug design.

Quassinoids are highly oxygenated triterpenes, which were isolated as bitter principles from the plants of Simaroubaceae family. Their synthesis has attracted much attention because of the wide spectrum of their biological properties. The most prevalent quassinoids have C-20 picrasane skeleton, some known as bruceolides as they were isolated from the genus Brucea, which showed marked antileukemic and antimalarial activities.

Synthesis of A/B-ring partial analogs of bruceantin as potential antimalarial agents.

Bruceantin (1), a classical quassinoid with the highest reported antimalarial activity among the quassinoids examined thus far, was selected as a natural product lead for the design of a series of A/B-ring analogs. A viable strategy for the synthesis of the series was developed. The functionalized A-ring and the C-15 ester moiety in bruceantin are incorporated in all designed compounds. The preliminary bioassay results will be discussed in detail.

Hydroxamic acids as pharmacological agents.

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

Enantioselective synthesis and complement inhibitory assay of A/B-ring partial analogues of oleanolic acid.

A series of oleanolic acid A/B-ring partial analogues was synthesized and tested for their complement inhibitory activity as well as cytotoxic properties. All target compounds and one intermediate exhibited moderate complement inhibitory potency. These compounds also showed cytotoxicity on malignant melanoma cell line, SK-MEL.

Effects of the inspiratory pressure waveform during patient-triggered ventilation on pulmonary stretch receptor and phrenic nerve activity in cats.

OBJECTIVE: To examine the effects of square wave, sinusoidal, and linear inspiratory pressure waveforms during pressure-controlled assist/control ventilation on the firing pattern of pulmonary stretch receptors and phrenic nerve activity. DESIGN: Experimental, comparative study. SETTING: Research laboratory at a university biomedical center. SUBJECTS: Nine anesthetized, endotracheally intubated young cats (2.5-3.4 kg). INTERVENTION: With interposed periods of continuous positive airway pressure (0.2 kPa), each cat was exposed to periods of assist/control ventilation with three different pressure waveforms, where the peak inspiratory pressure (0.74 +/- 0.13 kPa), end-expiratory pressure (0.2 +/- 0.02 kPa), and tidal volume (14.9 +/- 5.22 mL/kg) were kept constant. Preset controlled ventilator rate was set below the rate of spontaneous breathing, and the mechanical inflation time equaled the inspiratory time during spontaneous breathing on continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS: Respiratory rate and arterial blood gases did not change between the three pressure waveforms during assist/control ventilation. Peak pulmonary stretch receptor activity was lower and mean phrenic nerve activity higher during continuous positive airway pressure than during assist/control ventilation (p <.05). Peak inspiratory pulmonary stretch receptor activity was the same with all three pressure waveforms (82 +/- 17 impulses.sec-1) but occurred earlier with square wave than with sinusoidal or linear pressure waveforms (p <.05). The total number of impulses in the phrenic nerve activity burst was smaller with square wave than with the other two pressure waveforms (0.21 +/- 0.17 vs. 0.33 +/- 0.27 and 0.42 +/- 0.30 arbitrary units; p <.05), and the phrenic nerve activity burst duration was shorter with square wave (1.10 +/- 0.45 vs. 1.54 +/- 0.36 and 1.64 +/- 0.25 secs; p <.05). CONCLUSION: Square wave pressure waveform during pressure-controlled assist/control ventilation strongly inhibits spontaneous inspiratory activity in cats. One mechanism for this inhibition is earlier and sustained peak pulmonary stretch receptor activity during inspiration. These findings show that differences in inspiratory pressure waveforms influence the spontaneous breathing effort during assist/control ventilation in cats.

Material properties of trabecular bone structures.

The transplantation of human allograft for restoration and filling of cortical bone defects is well known. Our aim was an experimental investigation of the mechanical stability of the often used femoral head spongiosa depending on the caliber and extent of the allograft. To evaluate the orientation of the trabecular structures of the femoral head and relate this data to its mechanical properties, morphometric studies were combined with mechanical tests of cancellous bone specimens. The mechanical examination of the allograft was done following the compression test according to DIN 50106. We examined 36 human unfixed hip joint spongiosa cylinders with a height of 11 mm and a diameter of 24 mm. We took three specimens from each femoral head. We compressed the allograft at a constant velocity of 0.017 mm/sec. We calculated the maximum compression strength, the yield point and the Young's modulus. We also examined 12 parallelepipedic specimens with (17 x 17 x 51 mm) for morphometric analysis and loading in the direction of the primary compressive group (PCG), as well as perpendicular loading and at an angle of 45 degrees. We found divergent mechanical stabilities. None of the femoral heads showed comparable compressive strength. There was no position dependency of the strength of the samples. No relation between optical appearance and strength was found. We found a value for the lower compressive strength, which can be used for calculation as a basic value for safe constructions. Furthermore we tested the well known dependence of strength on the direction of the trabecular structure. We found a strong relationship between strength and load direction on the preferred direction of the trabecular structure. The sole recommendation resulting from our investigations is to rely on the lowest compressive strength for all preoperative planning. Relying on higher compressive strength by using the theoretical predicted areas of higher strength is hazardous since we found no correlation between position of sampling and strength. The size of our samples is important, because of the fact that different sizes of the samples might cause different failure mechanisms in the samples. The preparation of the femoral head spongiosa should be done according to the primary compressive group of the trabecular structure.

Synthesis and evaluation of potential complement inhibitory semisynthetic analogs of oleanolic acid.

A number of semisynthetic analogs of oleanolic acid have been synthesized and tested for their complement inhibitory, cytotoxic and apoptotic activities. Among these, compounds 10 and 17 exhibited complement inhibitory potency superior to oleanolic acid. Both have also shown a moderate improvement in in vitro therapeutic index (T.I.).

Assisted mechanical ventilation using combined elastic and resistive unloading in cats with severe respiratory failure: effects on gas exchange and phrenic nerve activity.

This study tests the efficacy of respiratory mechanical unloading as a mode of assisted mechanical ventilation in cats with an intact breathing-control system but severe pulmonary parenchymal injury. Twelve anaesthetized, intubated cats received multiple saline lung lavages so that their total respiratory system compliance decreased from 56.1+/-10.4 to 26.8+/-6.8 ml/kPa (p < 0.001) and their PaO2 fell to 12.38+/-4.71 kPa when 100% O2 was used as inspired gas. They were then exposed to three consecutive 15-min periods of CPAP of 0.5 kPa, respiratory unloading and again CPAP of 0.5 kPa. Unloading was applied with end-expiratory pressure of 0.5 kPa, elastic assistance of 0.03 kPa/ml and resistance compensation of 2.0 kPa/l/s. Arterial blood gases for the CPAP baselines did not differ significantly before and after unloading: pH 7.14+/-0.04 vs. 7.16+/-0.06; PaCO2 8.99+/-2.07 vs. 8.33+/-2.01 kPa; PaO2 12.4+/-4.7 vs. 13.3+/-7.6 kPa. Nor did the baselines differ in terms of tidal volume, respiratory rate and phrenic nerve activity. Unloading increased tidal volume substantially by about 50% and increased respiratory rate slightly, while inspiratory time remained unchanged. PaCO2 fell to 6.63+/-1.57 kPa and pH rose to 7.25+/-0.06. Phrenic nerve activity was significantly down-regulated in terms of total number of impulses and mean impulse frequency in the phrenic nerve burst. These results suggest that combined elastic and resistive unloading may be an effective means of assisted mechanical ventilation in severe respiratory failure of pulmonary parenchymal origin.

A new quassinoid from Castela texana.

A new quassinoid, 11-O-trans-p-coumaroyl amarolide (1) was isolated from Castela texana, and the structure was elucidated by spectroscopic analysis. Compound 1 is the first coumaroyl quassinoid derivative to have been isolated from nature. The known compounds amarolide (2), chaparrinone, chaparrin, glaucarubolone, holacanthone, and 15-O-beta-D-glucopyranosyl glaucarubol were also isolated. All isolated compounds were tested for their cytotoxicity and antiprotozoal activities.

Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors.

The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydrox y-2',5',5', 8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt 1c (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement, and 1c was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of 1a,c, the natural product was used as a "topographical model" for the design of partial analogs retaining the desired complement inhibiting potency. Therefore, A/C/D-ring analogs have been synthesized, as shown in Scheme 1 using 3-methoxyphenol (3) and limonene chloride (5) as starting materials, which contain functional groups similar to those found on the natural product. The use of (4R)-(+)- and (4S)(-)-limonene chloride (5a,b, respectively) provided two series of compounds differing in the stereochemistry of the C-4 chiral center (limonene moiety numbering). The in vitro assay results of the inhibition of anaphylatoxin production and classical complement-mediated hemolysis revealed that 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'R)-yl)-4-met hoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'S)-yl)-4-met hoxybenzofuran (13b) were active in the same range of concentrations as the natural product.

Cultivation of Tripterygium wilfordii Tissue Cultures for the Production of the Cytotoxic Diterpene Tripdiolide.

The production of the cytotoxic agent tripdiolide employing plant tissue cultures of TRIPTERYGIUM WILFORDII is demonstrated. Detailed investigations of a developed cell line of T. WILFORDII in terms of tripdiolide production versus variations in growth conditions, for example media composition, are presented. Also the age and size of the inoculum and the incubation period with respect to tripdiolide formation are evaluated.

2-Amino-4,7-dimethoxyindan derivatives: synthesis and assessment of dopaminergic and cardiovascular actions.

N-Alkylated derivatives of 2-amino-4,7-dimethoxyindan were prepared for evaluation of central and peripheral dopaminergic activity using biochemical and behavioral tests in the rat and cardiovascular responses in the cat. 2-(Di-n-propylamino)-4,7-dimethoxyindan (4e) demonstrated equal activity with apomorphine to activate peripheral presynaptic dopamine receptors. Central pre- and postsynaptic dopamine receptors were also activated with 4e. In contrast to the intense long-acting sympathomimetic actions previously reported for the 2-amino-5,8-dimethoxytetralins, these compounds produced weak, transient effects in heart rate and blood pressure. The majority of 2-amino-4,7-dimethoxyindan derivatives tested are weak or inactive pre- and postsynaptic dopamine receptor agonists.

N-demethylation of nicotine and reduction of nicotine-1'-N-oxide by Microsporum gypseum.

Several microorganisms were examined for their abilities to convert S-nicotine into nornicotine. Five microorganisms including Microsporum gypseum (ATCC 11395) produced nornicotine and three unknown metabolites. M. gypseum efficiently reduced nicotine-1'-N-oxide to nicotine, but no nornicotine was obtained when the N-oxide was used as substrate.