Maternal engineered nanomaterial inhalation during gestation alters the fetal transcriptome.

BACKGROUND: The integration of engineered nanomaterials (ENM) is well-established and widespread in clinical, commercial, and domestic applications. Cardiovascular dysfunctions have been reported in adult populations after exposure to a variety of ENM. As the diversity of these exposures continues to increase, the fetal ramifications of maternal exposures have yet to be determined. We, and others, have explored the consequences of ENM inhalation during gestation and identified many cardiovascular and metabolic outcomes in the F1 generation. The purpose of these studies was to identify genetic alterations in the F1 generation of Sprague-Dawley rats that result from maternal ENM inhalation during gestation. Pregnant dams were exposed to nano-titanium dioxide (nano-TiO2) aerosols (10 ± 0.5 mg/m3) for 7-8 days (calculated, cumulative lung deposition = 217 ± 1 µg) and on GD (gestational day) 20 fetal hearts were isolated. DNA was extracted and immunoprecipitated with modified chromatin marks histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3). Following chromatin immunoprecipitation (ChIP), DNA fragments were sequenced. RNA from fetal hearts was purified and prepared for RNA sequencing and transcriptomic analysis. Ingenuity Pathway Analysis (IPA) was then used to identify pathways most modified by gestational ENM exposure. RESULTS: The results of the sequencing experiments provide initial evidence that significant epigenetic and transcriptomic changes occur in the cardiac tissue of maternal nano-TiO2 exposed progeny. The most notable alterations in major biologic systems included immune adaptation and organismal growth. Changes in normal physiology were linked with other tissues, including liver and kidneys. CONCLUSIONS: These results are the first evidence that maternal ENM inhalation impacts the fetal epigenome.

[Optimizing the antibiotics policy in The Netherlands. VIII. Revised SWAB guidelines for antimicrobial therapy in adults with community-acquired pneumonia]. / Optimaliseren van het antibioticabeleid in Nederland. VIII. Herziene SWAB-richtlijnen voor antimicrobiële therapie bij thuis opgelopen pneumonie.

The Dutch Working Party on Antibiotic Policy (SWAB) has revised the 1998 guideline for community-acquired pneumonia (CAP) in light of changing resistance patterns for common pathogens and new developments in epidemiology, diagnostic testing and treatment strategies. The current guideline is applicable to both primary and inpatient care, and has been developed by delegates of all professional organisations involved in the treatment of CAP, following recommendations for evidence-based guideline development. Assessment of a patient's 'severity of illness' at presentation is considered important when choosing an optimal empirical antibiotic regimen for CAP. Severely-ill patients should be treated with antibiotics covering the most important expected pathogens, including Legionella. Assessment of the severity of illness may be facilitated by the use of validated scoring systems like the pneumonia severity index and the 'confusion, urea, respiratory-rate, blood-pressure, 65-years-of-age' (CURB-65) score. Patients can also be stratified based on their location during treatment: in the community, a normal ward or an intensive-care unit. Legionella urine antigen testing is considered an important tool in the process of deciding on an optimal antibiotic regimen for CAP. Empirical therapy should be replaced with pathogen-directed therapy if the causative agent is identified.

Revised SWAB guidelines for antimicrobial therapy of community-acquired pneumonia.

The Dutch Working Party on Antibiotic Policy (SWAB) develops evidence-based guidelines, aimed at optimalisation of antibiotic use and limitation of the spread of antimicrobial resistance. A revision of the SWAB guideline for the treatment of community-acquired pneumonia (CAP), published in 1998, was considered necessary because of changes in resistance patterns and new insights into the epidemiology, diagnostics and treatment of CAP. In contrast to the former version, this guideline is transmural and has been drawn up according to the recommendations for evidence-based guideline development by a multidisciplinary committee consisting of experts from all relevant professional societies. The 'severity of disease' exhibited by the patient with pneumonia on admission is considered important for the choice of the optimum empirical treatment strategy. Severely ill patients are treated empirically with a drug directed against multiple potential pathogens, including Legionella spp. Classification according to 'severity of disease' can be accomplished with a validated scoring system (Pneumonia Severity Index or CURB-65 score) or pragmatically, based on the site of treatment: an outpatient setting, a clinical ward or an intensive care unit. The Legionella urine antigen test plays an important role in decisions on the choice of initial antibiotic treatment.

Exercise down-regulates hepatic fatty acid synthase in streptozotocin-treated rats.

An acute bout of prolonged exercise has been shown to decrease hepatic fatty acid synthase (FAS) mRNA and activity induced by high carbohydrate diets. The purpose of the current study was to examine the role of insulin in this exercise down-regulation of FAS. Sixty-four male Wistar rats were randomly divided into normal and streptozotocin (STZ)-treated diabetic groups. After being starved for 48 h and refed a high cornstarch (C) or fructose (F) diet for 10 h, one half of each group of rats was killed after an acute bout of prolonged exercise (E), while the other half of the group was killed in the rested state. STZ treatment suppressed plasma insulin and elevated plasma glucagon levels along with a severe hyperglycemia. FAS mRNA levels decreased by 60% (P < 0.05) with STZ treatment but were 250% higher in F-fed versus C-fed rats. E abolished F-induced FAS mRNA levels in both normal and STZ rats and decreased plasma glucose concentration in STZ rats (P < 0.05). F-fed normal rats showed twofold higher hepatic FAS activity than did C-fed normal rats and this dietary induction was abolished by STZ (P < 0.05). FAS activity in normal rats was not affect by E and was increased with E in STZ rats. Nuclear protein binding to the insulin response sequence was not affected by STZ or diet and increased with E (P < 0.05). Carbohydrate response element binding was greater with F- versus C-feeding (P < 0.05) but unaffected by E. E enhanced inverted CCAAT-box element binding regardless of diet and STZ. We conclude that although insulin status had a great influence on FAS gene expression, E-induced down-regulation of FAS mRNA was not mediated by altered insulin response sequence binding but primarily by increased inverted CCAAT-box element binding to the FAS promoter and/or decreased concentration of carbohydrate metabolites.

Pharmacokinetics of alfentanil before and after cardiopulmonary bypass in pediatric patients undergoing cardiac surgery: Part I.

Changes induced by cardiopulmonary bypass (CPB) may markedly affect the pharmacokinetics of drugs. Therefore, the pharmacokinetics of alfentanil before and after CPB were compared in infants and children undergoing cardiac surgery, who had been anesthetized with nitrous oxide in oxygen and low inspiratory concentrations of halothane. Six infants and six children were investigated. Before CPB, alfentanil, 200 micrograms/kg, and after CPB, alfentanil, 80 micrograms/kg, was infused in 10 minutes. Arterial blood samples were obtained before and after CPB for determination of plasma alfentanil concentrations. Bi-exponential functions were fitted to the plasma concentration-time data using weighted least-squares nonlinear regression analysis. A correction was made to account for the contribution of the first infusion to the plasma concentrations measured during and after the second infusion. Total sampling time before CPB (45 to 75 minutes) was too short to allow full characterization of the pharmacokinetics of alfentanil, but allowed estimation of the initial volume of distribution. The initial volume of distribution before CPB was smaller (68 +/- 37 mL/kg in infants and 80 +/- 32 mL/kg in children) than after CPB (235 +/- 58 mL/kg in infants and 179 +/- 99 mL/kg in children; P less than 0.001). The normalized area under the plasma concentration-time curve from 0 to 45 minutes was larger before CPB (17.9 +/- 2.9 mg.min/L in infants and 18.3 +/- 5.4 mg.min/L in children) than after CPB (11.1 +/- 2.9 mg.min/L in infants and 12.9 +/- 3.4 mg.min/L in children; P less than 0.001). Despite intravenous administration of atropine, arterial blood pressure and heart rate decreased significantly after alfentanil was given.

Pharmacokinetics of alfentanil before and after cardiopulmonary bypass in pigs: Part II.

The pharmacokinetics of alfentanil before and after cardiopulmonary bypass (CPB) were investigated in six pigs undergoing mitral valve replacement. Before bypass, alfentanil, 100 micrograms/kg, was infused in 10 minutes and after bypass, alfentanil, 40 micrograms/kg, was infused in 10 minutes. Low inspiratory concentrations of halothane were given concomitantly. Arterial blood was obtained before and after CPB for determination of plasma alfentanil concentrations by gas chromatography. Bi-exponential functions were fitted to the plasma concentration-time data using weighted least-squares nonlinear regression analysis. The steady-state volume of distribution (Vss; 258 +/- 70 mL/kg), elimination clearance (Cle; 10.7 +/- 3.0 mL/kg/min), and distribution clearance (Cld; 6.8 +/- 3.3 mL/kg/min) before CPB were smaller than the Vss (1,107 +/- 373 mL/kg; P less than 0.01), Cle (20.0 +/- 3.0 mL/kg/min; P less than 0.002), and Cld (23.0 +/- 6.7 mL/kg/min; P less than 0.02) after CPB. The distribution half-life (t1/2 lambda 1; 2.8 +/- 0.8 minutes) was longer and the elimination half-life (t1/2 lambda 2; 36 +/- 8 minutes) was shorter before CPB than the t1/2 lambda 1 (1.7 +/- 0.2 minutes; P less than 0.05) and t1/2 lambda 2 (68 +/- 20 minutes; P less than 0.02) after CPB.

Alfentanil in infants and children with congenital heart defects.

The use of an alfentanil infusion as a supplement to a nitrous oxide-halothane anesthetic and the pharmacokinetics of alfentanil were evaluated in infants and children undergoing surgery for correction of congenital heart defects. Eleven patients, six infants and five children, were studied. Anesthesia was induced with nitrous oxide-halothane and pancuronium, 0.15 mg/kg. After intubation, anesthesia was maintained with nitrous oxide-oxygen and halothane to a maximum inspired concentration of 0.6%. After administration of atropine, 20 micrograms/kg, alfentanil, 20 micrograms/kg, was given, followed by a continuous infusion of 1 microgram/kg/min, which was stopped after closure of the sternum. Supplemental boluses of alfentanil, 5 micrograms/kg, were given when, during surgery, blood pressure and/or heart rate increased more than 20% above control values. At the end of surgery, after antagonism of residual neuromuscular blockade, the patients were extubated. Arterial blood samples were collected at regular intervals during surgery and for six hours thereafter for determination of alfentanil plasma concentrations by gas chromatography. Pharmacokinetic data were calculated using the method of residuals and noncompartmental moment analysis. Although atropine was administered, heart rate decreased significantly (2.5% to 15%) in all infants after administration of alfentanil. In the older children, blood pressure decreased 10% to 35%. In the period before bypass, three infants and four children needed supplemental boluses of alfentanil. During and after bypass, anesthesia was adequate. All patients could be extubed within 34 minutes of stopping the alfentanil infusion. Naloxone was not required in any patient, and postoperative respiratory depression did not occur. In the infants and children, total plasma clearance was 8.2 +/- 2.2 mL/kg/min and 6.3 +/- 0.8 mL/kg/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance therapy after i.v. administration of disopyramide with an oral sustained release preparation, a pharmacokinetic study.

The blood levels in 20 patients were studied during the change from parenteral administration of disopyramide to an oral sustained release preparation containing the same active substance. From this study it is concluded that 100 mg i.v. bolus injection of disopyramide can safely be followed by the immediate administration of one sustained release tablet containing 250 mg disopyramide. In case of an i.v. infusion (0.4 mg kg-1h-1) it seems wise not to start earlier with the administration of the sustained release preparation than at the moment of stopping the infusion.

Chemical bonding information from photoelectron spectroscopy.

High-resolution measurements of photoelectrons produced by x-rays in compounds of iodine and europium have revealed chemical shifts in the core-level energies, from which chemical bonding information can be obtained. The observed shifts, 0.8 electron volt per unit change in oxidation number in iodine and 9.6 electron volts in europium, are discussed in terms of two theoretical models.