Effect of a preemptive femoral nerve block on cytokine release and hyperalgesia in experimentally inflamed skin of human volunteers.

Background And Objectives: Tissue injury is associated with the local release of inflammatory and nociceptive mediators and the development of hyperalgesia. It is unclear whether interrupting neuronal signaling using regional anesthetic techniques at the time of the injury modifies local nociceptive and inflammatory processes. The aim of this study was to determine whether a peripheral nerve block at the time of tissue injury could modify the development of wound hyperalgesia and the local release of inflammatory and nociceptive mediators.

Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD.

Surfactant protein (SP)-D is a lung-derived protein that has been proposed as a biomarker for inflammatory lung disease. Serum SP-D was evaluated as a biomarker for components of chronic obstructive pulmonary disease (COPD) in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort and its response assessed to the administration of the anti-inflammatory agent prednisolone. The median level of serum SP-D was significantly elevated in 1,888 individuals with COPD compared to 296 current and former smokers without airflow obstruction (121.

A randomized trial of maximum cephalad sensory blockade with single-shot spinal compared with combined spinal-epidural techniques for cesarean delivery.

Background: Previous studies have shown more extensive cephalad sensory blockade in women receiving combined spinal-epidural (CSE) anesthesia compared with single-shot spinal (SSS) anesthesia for elective cesarean delivery. It has been postulated that introduction of the epidural needle during CSE disturbs the negative pressure in the epidural space, resulting in relatively greater cerebrospinal fluid (CSF) pressure and increased spread of intrathecal local anesthetic. We tested the hypothesis that CSE results in more extensive cephalad sensory blockade than SSS anesthesia and that loss-of-resistance during initiation of CSE anesthesia increases CSF pressure compared with SSS.

Variability of target-controlled infusion is less than the variability after bolus injection.

Background: Target-controlled infusion (TCI) drug delivery systems deliver intravenous drugs based on pharmacokinetic models. TCI devices administer a bolus, followed by exponentially declining infusions, to rapidly achieve and maintain pseudo-steady state drug concentrations in the plasma or at the site of drug effect. Many studies have documented the prediction accuracy of TCI devices.

The bronchodilator response to salmeterol is maintained with regular, long-term use in patients with COPD.

Long-acting beta(2)-agonists (LABAs) are recommended in the management of patients with chronic obstructive pulmonary disease (COPD). Previous studies have demonstrated that the LABA, salmeterol, improves lung function, symptoms and quality of life in patients with COPD. In this study, we have performed additional analyses of the combined data from two previous double-blind, placebo-controlled, parallel studies of salmeterol (50 microg, b.

The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD.

Study Objectives: To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate (FP) and the inhaled long-acting beta(2)-agonist salmeterol (SM), when administered together in a single device (Diskus; GlaxoSmithKline, Inc; Research Triangle Park, NC), with that of placebo and the individual agents alone in patients with COPD.

Design: Randomized, double-blind, multicenter, placebo-controlled study.

Setting: Seventy-six investigative sites in the United States.

Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain.

Increased circulating cholesterol is known to promote risk of coronary artery disease. It is now emerging that cholesterol promotes production and accumulation of amyloid beta (Abeta) deposited in the hallmark pathologic lesion of Alzheimer's disease (AD), the senile plaque, perhaps by shifting away from normal metabolism of amyloid beta protein precursor (AbetaPP) to beta. Previous studies employing the cholesterol-fed rabbit model of AD demonstrated that induction of AD-like Abeta accumulation in brain could be reversed by co-administration of cholesterol lowering drugs or removing cholesterol, prompted initiation of an AD Cholesterol-Lowering (Statin) Treatment Trial.

Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease.

This randomized controlled trial examined the benefits of combining an inhaled corticosteroid, fluticasone propionate (F), with an inhaled long-acting beta(2)-agonist, salmeterol (S), to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease (COPD). A total of 691 patients with COPD received the combination of F and S (FSC), S (50 mcg), F (500 mcg), or placebo twice daily via the Diskus device for 24 weeks. A significantly greater increase in predose FEV(1) at the endpoint was observed after FSC (156 ml) compared with S (107 ml, p = 0.

Role of nitric oxide in heparin-induced attenuation of hypoxic pulmonary vascular remodeling.

Heparin and nitric oxide (NO) attenuate changes to the pulmonary vasculature caused by prolonged hypoxia. Heparin may increase NO; therefore, we hypothesized that heparin may attenuate hypoxia-induced pulmonary vascular remodeling via a NO-mediated mechanism. In vivo, rats were exposed to normoxia (N) or hypoxia (H; 10% O(2)) with or without heparin (1,200 U x kg-1 x day-1) and/or the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg x kg-1 x day-1) for 3 days or 3 wk.

Effect of antioxidant supplementation on ozone-induced lung injury in human subjects.

To determine whether antioxidants can influence human susceptibility to ozone (O(3))-induced changes in lung function and airway inflammation, we placed 31 healthy nonsmoking adults (18 to 35 yr old) on a diet low in ascorbate for 3 wk. At 1 wk, subjects were exposed to filtered air for 2 h while exercising (20 L/min/m(2)), and then underwent bronchoalveolar lavage (BAL) and were randomly assigned to receive either a placebo or 250 mg of vitamin C, 50 IU of alpha-tocopherol, and 12 oz of vegetable cocktail daily for 2 wk. Subjects were then exposed to 0.

Cyclooxygenase inhibitors attenuate bradykinin-induced vasoconstriction in septic isolated rat lungs.

Unlabelled: Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control).

Selective iNOS inhibition attenuates acetylcholine- and bradykinin-induced vasoconstriction in lipopolysaccharide-exposed rat lungs.

Background: Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction.

Methods: Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg).

Increased specific airway reactivity of persons with mild allergic asthma after 7.6 hours of exposure to 0.16 ppm ozone.

Background: Exposure to ozone causes decrements in lung function, increased airway reactivity to nonspecific bronchoconstrictors, and lung inflammation. Epidemiology studies show an association between ambient oxidant levels and increased asthma attacks and hospital admissions.

Objective: The purpose of our study was to evaluate the response of persons with mild asthma to inhaled allergen after ozone exposure conditions similar to those observed in urban areas of the United States.

Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats.

Unlabelled: Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1).

Aminoguanidine inhibits inducible NOS and reverses cardiac dysfunction late after ischemia and reperfusion--implications for iNOS-mediated myocardial stunning.

Background: The functional significance of inducible nitric oxide synthase (iNOS) activation in response to myocardial ischemia and reperfusion (I/R) was investigated.

Methods: New Zealand rabbits were randomly treated with either placebo, aminoguanidine (AMG; selective iNOS inhibitor), or L-arginine. Left-ventricular hemodynamics and myocardial blood flow were measured before coronary occlusion and 30 minutes and 48 h after initiation of reperfusion.

Inflammatory response in humans exposed to 2.0 ppm nitrogen dioxide.

Nitrogen dioxide (NO2) is a common indoor air pollutant, especially in homes with unvented combustion appliances. Epidemiological studies suggest that children living in homes with unvented heating sources are more prone to respiratory infections than children living in homes with lower levels of NO2. However, experimental studies in which human volunteers were exposed acutely to moderate levels of NO2 (0.

Action of phosphatidylinositol-specific phospholipase Cgamma1 on soluble and micellar substrates. Separating effects on catalysis from modulation of the surface.

The kinetics of PI-PLCgamma1 toward a water-soluble substrate (inositol 1,2-cyclic phosphate, cIP) and phosphatidylinositol (PI) in detergent mixed micelles were monitored by 31P NMR spectroscopy. That cIP is also a substrate (Km = approximately 15 mM) implies a two-step mechanism (intramolecular phosphotransferase reaction to form cIP followed by cyclic phosphodiesterase activity to form inositol-1-phosphate (I-1-P)). PI is cleaved by PI-PLCgamma1 to form cIP and I-1-P with the enzyme specific activity and ratio of products (cIP/I-1-P) regulated by assay temperature, pH, Ca2+, and other amphiphilic additives.

The influence of deletion mutations on phospholipase C-gamma 1 activity.

Phospholipase C-gamma1, a substrate for many growth factor receptor and nonreceptor tyrosine kinases, produces second messenger molecules that are elements of signal transduction pathways related to cell proliferation. The influence of deletion mutations, which do not intrude on the domains required for catalytic function, on the basal activity of this enzyme is reported. Removal of the first 74 amino-terminal residues increases phospholipase C activity, while deletion of the carboxy-terminal 81 residues decreases enzyme activity.

The effect of prolonged inhaled nitric oxide on pulmonary vasoconstriction in rats.

Unlabelled: Down-regulation of the endogenous nitric oxide (NO) pathway may explain rebound pulmonary hypertension after discontinuation of inhaled NO. We determined whether the prolonged administration of inhaled NO increases pulmonary vasoconstriction, which may occur from decreased endogenous NO. Rats were placed in normoxic (N; 21% O2) or hypoxic (H; 10% O2) chambers with or without inhaled NO (20 ppm) for 1 or 3 wk.

Regulation of the endogenous NO pathway by prolonged inhaled NO in rats.

Nitric oxide (NO) modulates the endogenous NO-cGMP pathway. We determined whether prolonged inhaled NO downregulates the NO-cGMP pathway, which may explain clinically observed rebound pulmonary hypertension. Rats were placed in a normoxic (N; 21% O2) or hypoxic (H; 10% O2) environment with and without inhaled NO (20 parts/million) for 1 or 3 wk.

Nitric oxide synthase inhibitors alter ventilation in isoflurane anesthetized rats.

Background: Nitric oxide (NO) is present in medullary structures and can modulate respiratory rhythm. The authors determined if spontaneous ventilation at rest and in response to increased carbon dioxide is altered by selective neuronal NO synthase (NOS; 7-nitro-indazole, 7-NI) or nonselective (neuronal plus endothelial) NOS (NG-L-arginine methyl ester [L-NAME] and NG-monomethyl L-arginine [L-NMMA]) inhibitors in rats anesthetized with isoflurane.

Methods: Fifty-four rats received either L-NAME or L-NMMA (1, 10, and 30 mg/kg) or 7-NI (20, 80, and 400 mg/kg) and were compared with time controls (isoflurane = 1.

Prolonged acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in asthmatic subjects with allergies.

Background: Increased ambient ozone levels have been associated with increased asthma morbidity in epidemiologic studies. Given that asthma is characterized by airway inflammation and increased sensitivity to airway irritants, it has been suggested that asthmatic subjects may be particularly sensitive to the effect of ozone.

Objective: The objective of this study was to determine whether exposure to 0.

Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats.

Unlabelled: In concentrations of 10-20 ppm, inhaled nitric oxide (NO) decreases pulmonary artery pressure and attenuates vascular remodeling in pulmonary hypertensive rats. Because NO is potentially toxic, it is important to know whether lower concentrations attenuate vascular remodeling produced by different etiologies. Therefore, we determined the effects of prolonged, small-dose inhaled NO administration on hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling.

Selective modulation of inducible nitric oxide synthase isozyme in myocardial infarction.

Background: Inducible nitric oxide synthase (iNOS) is activated in cardiac disorders. We investigated the contribution of increased iNOS activity to the development of left ventricular dysfunction after myocardial infarction by selective inhibition of the isozyme.

Methods And Results: Male New Zealand rabbits were subjected to myocardial infarction.