ROS generated by pollen NADPH oxidase provide a signal that augments antigen-induced allergic airway inflammation

Pollen exposure induces allergic airway inflammation in sensitized subjects. The role of antigenic pollen proteins in the induction of allergic airway inflammation is well characterized, but the contribution of other constituents in pollen grains to this process is unknown. Here we show that pollen grains and their extracts contain intrinsic NADPH oxidases. The pollen NADPH oxidases rapidly increased the levels of ROS in lung epithelium as well as the amount of oxidized glutathione (GSSG) and 4-hydroxynonenal (4-HNE) in airway-lining fluid. These oxidases, as well as products of oxidative stress (such as GSSG and 4-HNE) generated by these enzymes, induced neutrophil recruitment to the airways independent of the adaptive immune response. Removal of pollen NADPH oxidase activity from the challenge material reduced antigen-induced allergic airway inflammation, the number of mucin-containing cells in airway epithelium, and antigen-specific IgE levels in sensitized mice. Furthermore, challenge with Amb a 1, the major antigen in ragweed pollen extract that does not possess NADPH oxidase activity, induced low-grade allergic airway inflammation. Addition of GSSG or 4-HNE to Amb a 1 challenge material boosted allergic airway inflammation. We propose that oxidative stress generated by pollen NADPH oxidases (signal 1) augments allergic airway inflammation induced by pollen antigen (signal 2).     

Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787

By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.     

Effects of nebivolol on left ventricular function in elderly patients with chronic heart failure: results of the ENECA study

AIM: To examine the effect of the beta(1)-selective beta-blocker nebivolol, administered as add-on therapy, on left ventricular function in 260 elderly patients (>65 years) with chronic heart failure (CHF). METHODS: The principal inclusion criteria were (1) NYHA class II-IV CHF and (2) a left ventricular ejection fraction (LVEF) <= 35%. The primary end-point was the change in LVEF in response to nebivolol treatment for 8 months. RESULTS: Baseline LVEF values in the two groups were as follows: nebivolol 25.41+/-7.09% and control 26.41+/-5.55%. LVEF improved significantly (p=0.027) more in the nebivolol group (6.51+/-9.15%) than in the control group (3.97+/-9.20%), the relative improvement (percentage increase in the initial value) being 35.70+/-57.62% in the nebivolol group and 19.19+/-40.96% (p=0.008) in the placebo group. Examination of different subgroups did not reveal any heterogeneity in the effects of nebivolol treatment vs. placebo treatment. There were no significant differences between the nebivolol and placebo groups as concerns the changes in clinical status, quality of life, or safety parameters. CONCLUSION: The findings of the ENECA study confirmed that nebivolol significantly improved cardiac function and proved to be safe and well tolerated in elderly patients with signs of CHF and an impaired LVEF.     

Molecular and Cellular Actions of Galantamine: Clinical Implications for Treatment of Organophosphorus Poisoning

There have been continued efforts to develop effective antidotal therapies against poisoning with organophosphorus (OP) compounds, including nerve agents and pesticides. We reported recently that galantamine, a drug used to treat Alzheimer’s disease, administered before (up to 3 h) or soon after (up to 5 min) an exposure of guinea pigs to 1.5–2?×?LD50 soman or sarin effectively counteracted the acute toxicity and lethality of the nerve agents provided that the animals were also post-treated with atropine. Here, we demonstrate that administered to guinea pigs at 30 min before or up to 15 min after an acute challenge with 1?×?LD50 soman, galantamine (8 mg/kg, intramuscular) alone is sufficient to counteract the lethality and acute toxicity of the nerve agent. Evidence is also provided that 100% survival can be attained when the association of appropriate doses of galantamine and atropine is administered 30–45 min after the challenge of the guinea pigs with 1?×?LD50 soman. Galantamine counteracts the neurodegeneration and the changes in the nicotinic cholinergic system that result from an acute exposure of guinea pigs to 1?×?LD50 soman. The results presented herein corroborate that galantamine is an effective antidote against OP poisoning.     

Human entorhinal gamma and theta oscillations selective for remote autobiographical memory

Current source densities in different layers of the human entorhinal cortex (ER) were recorded using a linear array of 24 microelectrodes during three memory conditions: a remote autobiographical condition eliciting recollections of events that occurred 10 or more years ago in the participant's past, a semantic icon condition invoking the mental image of a well‐known object, and a semantic knowledge condition asking about general information. Our data demonstrate theta, gamma, and delta oscillations in left ER particularly for remote autobiographical memory. Gamma is predominant in hippocampally projecting layers during presentation of the memory cue, whereas theta is prolonged and dominant in cortically projecting layers during memory retrieval. Gamma interactions between ER and hippocampal formation (HF) may elicit an HF contribution to recall under influences relayed from the association cortex (AC). This contribution may then be relayed back to AC during retrieval of the memory orchestrated by theta interactions with ER. Accordingly, theta oscillations were recorded simultaneously in frontal and temporal cortices. © 2009 Wiley‐Liss, Inc.     

Rapid sequence induction for appendectomies: a retrospective case-review analysis

Purpose

Rapid sequence induction (RSI) with cricoid pressure is suggested to decrease the risk of aspiration of gastric contents. However, the effectiveness of RSI has been questioned, and the technique may lead to airway and hemodynamic complications. The purpose of this study was to determine the frequency of RSI use in patients with acute appendicitis, the types of drugs administered, and the occurrence of any complications.

Methods

After approval by the Ethics Committee, the charts of patients undergoing appendectomy in a one-year period were examined retrospectively. Information was retrieved on Mallampati airway evaluation, airway device used, preoxygenation, RSI, and drugs at induction. Reported complications were noted, including airway difficulties, hypotension (systolic blood pressure < 80 mmHg) and hypertension (>160 mmHg) in the 20-min period after induction.

Results

General anesthesia with tracheal intubation was used in 248 of 250 cases reviewed. The Mallampati airway evaluation, preoxygenation, and RSI were recorded as performed in 95, 94, and 81% of cases, respectively. Opioids, propofol, and neuromuscular blocking agents were given in 98, 98, and 99% of patients, respectively. Succinylcholine use was common (80%), with 96% of these patients receiving rocuronium precurarization. Difficult intubation with successful alternate technique was encountered in three patients (1.2%). Hypotension and hypertension occurred in 27% and 8% of patients, respectively. There were no documented cases of aspiration. Oxygen desaturation was mentioned in one case at induction and in three cases at emergence.

Conclusion

An RSI with opioid, induction agent, and succinylcholine is the technique of choice for appendectomies at our institution. The frequency of airway complications is too low to recommend a change in practice.     

Sleep Apnea Is Associated with Cardiovascular Risk Factors among Kidney Transplant Patients

Background and objectives: We assessed the prevalence of obstructive sleep apnea (OSA) and its clinical correlates in a large sample of patients who received a kidney transplant (Tx). We also compared the prevalence of the disorder between dialysis patients who were on the waiting list for a Tx (WL) and Tx patients.Design, setting, participants, & measurements: This was a cross-sectional study of 100 Tx and 50 WL patients who underwent one-night polysomnography (SLeep disorders Evaluation in Patients after kidney Transplantation [SLEPT] Study). Sociodemographic information and data about medication, comorbidity, and laboratory parameters were collected.Results: The prevalence of mild (apnea-hypopnea index [AHI] ≥5/h and <15/h), moderate (AHI ≥15/h and <30/h), and severe OSA (AHI ≥30/h) was 18, 11, and 14% in the Tx group and 28, 16, and 10% in the WL group, respectively. The AHI was significantly correlated with age (ρ = 0.34), body mass index (ρ = 0.45), neck circumference (ρ = 0.4), abdominal circumference (ρ = 0.51), and hemoglobin (ρ = 0.24) in the Tx group. The proportion of Tx patients who were treated with three or more antihypertensive drugs was significantly higher in the OSA group (56 versus 31%; P = 0.022). Despite taking significantly more antihypertensive drugs, the average systolic BP was still higher in patients with versus without OSA (147 ± 21 versus 139 ± 18 mmHg; P = 0.059).Conclusions: The prevalence of OSA is similar in Tx and WL patients and it may contribute to presence of hypertension in patients who receive a Tx.Obstructive sleep apnea (OSA) is the most clinically important form of sleep-related breathing disorders. The severity of OSA is generally characterized by the apnea-hypopnea index (AHI), which is the number of apneic and hypopneic events per hour of sleep.The prevalence of moderate and severe OSA syndrome (OSAS; AHI ≥15 and the presence of daytime symptoms of OSA) is 2 to 4% in the general population (1) and is associated with increased cardiovascular morbidity and mortality (2,3). OSAS is reportedly associated with higher risk for stroke, hypertension, diabetes, congestive hearth failure, arrhythmias, and the metabolic syndrome and also with fatal and nonfatal cardiovascular events (4–7)Previous studies have shown high prevalence of OSA (16 to 54%) in patients with chronic kidney disease (CKD) (8,9). Unruh et al. (10) showed that OSA is more common in hemodialysis patients than in general population.Although OSA may contribute to the increased cardiovascular risk seen in Tx patients, consistent information about OSA in patients who have received a kidney transplant (Tx) is scarce. Previously, we found that the prevalence of high risk for OSAS is approximately 30% in both WL and Tx patients (11). A case series indicated that AHI did not change after transplantation in 73% of the patients (12). Conversely, Mallamaci et al. (13) recently reported that 22% of renal Tx recipients had a respiratory disturbance index >5, which was similar to results seen in the general population.We designed this cross-sectional study to determine the prevalence and clinical correlates of OSA in a large, randomly selected sample of Tx patients using polysomnography. On the basis of our previous findings, we hypothesized that the prevalence of OSA would be similarly high in Tx and WL patients. Finally, we expected to find an increased cardio- and cerebrovascular risk in patients with versus without OSA in the Tx population.     

Lipoamino acids as major components of absorption promoters in drug delivery

Many biologically active compounds are unsuitable for development as drugs due to their poor bioavailability. For hydrophilic compounds, modifications to increase lipophilicity can increase passive diffusion or increase uptake into the lymphatic system. Alternatively, improved bioavailability of hydrophilic drug candidates may be achieved by formulation with absorption promoters such as surfactants, penetration enhancers, or ion pairing agents. This approach to enhancing bioavailability also has the potential to widen the range of compound categories that can be used as chemical probes to study biological systems in cells and in vivo where membrane permeability would otherwise be a significant limitation. Lipidic amino acids, which combine the structural properties of lipids with those of α-amino acids, represent a relatively unexplored class of agents that can improve drug adsorption. This review discusses the potential of absorption promoters possessing lipoamino acids for improving drug bioavailability.