Lung surfactants.

PURPOSE: The pharmacology, clinical efficacy, and cost considerations of exogenous lung surfactants are reviewed. SUMMARY: Exogenous pulmonary surfactants, along with advancements in ventilatory care, have significantly reduced the incidence of respiratory distress syndrome (RDS) and its related complications in infants. The following exogenous surfactants are approved for the prophylaxis and treatment (rescue) of neonatal RDS: beractant, a modified natural surfactant; calfactant and poractant, both natural surfactants; and colfosceril, a synthetic surfactant that is not currently available in the United States. Lucinactant, a synthetic surfactant, is under investigation and received approvable status from the Food and Drug Administration in February 2005. The surfactants are delivered directly to their site of action, and only small amounts reach the systemic circulation. Bioavailability to the distal airways and alveoli depends on the method of delivery, the stage and severity of pulmonary disease, and the properties of the particular surfactant. According to data from clinical trials, the use of exogenous surfactant therapy for rescue within the first two hours of life appears to be as efficacious as prophylaxis in most premature infants. CONCLUSION: Comparative trials of surfactants have proven the efficacy of both synthetic and natural surfactants in the prevention and treatment of RDS. However, these trials have universally demonstrated greater reduction in the immediate need for ventilator support in infants who receive natural surfactants. Natural preparations cause less pneumothorax, bronchopulmonary dysplasia, and mortality compared with synthetic preparations. Synthetic agents offer the potential advantages of an unlimited supply with consistent pharmaceutical quality and no risk of transmitting infectious disease or causing immunologic sensitization.     

Frequency and determinants of flare and persistently active disease in systemic lupus erythematosus

Objective

Selection of flare as the primary outcome variable in systemic lupus erythematosus (SLE) clinical trials fails to capture patients with persistently active disease (PAD). We sought to elucidate the frequency and determinants of flare and PAD.

Methods

Prospectively collected data from the Toronto Lupus Cohort were used to determine the incidence of flare and PAD in 2004 and 2005. Flare was defined as an increase in SLE Disease Activity Index 2000 update (SLEDAI‐2K) score of ≥4 from the previous visit. PAD was defined as a SLEDAI‐2K score of ≥4, excluding serology alone, on ≥2 consecutive visits. Data from 1, 2, and 3 years prior were used to model flare and PAD in 2004. Model properties were tested for prediction of flare and PAD in 2005.

Results

One‐third of the patients had ≥1 flare, whereas nearly half experienced PAD in a given year. Nearly 60% of the patients had episodes of flare or PAD per year. At least 25% of patients had PAD without achieving the definition of flare. In the best‐fitting model, predictors of PAD in 2004 were SLEDAI‐2K score at the start of the outcome interval and prior cutaneous or musculoskeletal disease activity. This model gave 79% correct prediction of PAD in 2005. In contrast, flare prediction models performed poorly.

Conclusion

Persistent activity is a common disease state in SLE and should be an outcome variable in SLE clinical trials. Our PAD prediction model may aid prognostication and selection of patients for inclusion in clinical trials.     

Effects of parecoxib on plasma protein extravasation and c-fos expression in the rat

OBJECTIVE: We aimed to investigate the effects of the cyclooxygenases-2 (COX-2) inhibitor parecoxib on meningeal plasma protein extravasation (PPE) and on c-fos expression in the nucleus trigeminalis caudalis in an animal model of trigeminovascular activation. Background.-Recent reports about the efficacy of COX-2 inhibitors in migraine treatment suggest the involvement of COX-2 in migraine pathophysiology. So far, studies on the role of COX-2 in animal models of migraine are lacking. METHODS: Unilateral electrical stimulation of the trigeminal ganglion was performed in anesthetized male Sprague Dawley rats. We assessed PPE in the ipsilateral dura mater and expression of c-fos within the ipsilateral trigeminal nucleus caudalis (TNC) under control conditions and after pretreatment with parecoxib. RESULTS: Parecoxib significantly attenuated PPE in the rat dura mater. The PPE ratio under control conditions (1.73 +/- 0.19 (mean +/- SD)) was reduced by 58.9 +/- 30% after pretreatment with 10 mg/kg parecoxib and by 78.1 +/- 23% after pretreatment with 50 mg/kg. c-fos experiments: Compared with vehicle, all doses of parecoxib (1 mg/kg, 10 mg/kg, 50 mg/kg) significantly reduced the number of c-fos positive cells in the ipsilateral TNC (P < .05). The number of c-fos positive cells in the ipsilateral TNC was 50 +/- 2.7 (mean +/- SEM) under control conditions and 9.1 +/- 0.6 after pretreatment with 50 mg/kg parecoxib. CONCLUSION: Our study results suggest that COX-2 is involved in neurogenic inflammation of the rat dura mater. Moreover, the study points to a role of COX-2 inhibitors in trigeminal nociception at the second-order level.     

Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells

The transmembrane ubiquitin ligase K5/MIR2 of Kaposi sarcoma herpesvirus (KSHV) mediates internalization and lysosomal degradation of glycoproteins involved in antigen presentation and co-stimulation. In endothelial cells (ECs), K5 additionally reduced expression of CD31/platelet-endothelial cell adhesion molecule (PECAM), an adhesion molecule regulating cell-cell interactions of ECs, platelets, monocytes, and T cells. K5 also reduced EC migration, a CD31-dependent process. Unlike other K5 substrates, both newly synthesized and pre-existing CD31 molecules were targeted by K5. K5 was transported to the cell surface and ubiquitinated pre-existing CD31, resulting in endocytosis and lysosomal degradation. In the endoplasmic reticulum, newly synthesized CD31 was degraded by proteasomes, which required binding of phosphofurin acidic cluster sorting protein-2 (PACS-2) to acidic residues in the carboxyterminal tail of K5. Thus, CD31, a novel target of K5, is efficiently removed from ECs by a dual degradation mechanism that is regulated by the subcellular sorting of the ubiquitin ligase. K5-mediated degradation of CD31 is likely to affect EC function in KS tumors.     

Autotransplantation of mesenchymal stromal cells from bone-marrow to heart in patients with severe stable coronary artery disease and refractory angina — Final 3-year follow-up

Background

The study assessed long-term safety and efficacy of intramyocardial injection of autologous bone-marrow derived mesenchymal stromal cells (BMMSCs) in patients with severe stable coronary artery disease (CAD) and refractory angina.

Methods

Thirty-one patients with severe stable CAD and refractory angina were included. Patients had reversible myocardial ischemia and no further revascularization options. Autologous BMMSCs were isolated, culture expanded and stimulated with vascular endothelial growth-factor to facilitate endothelial differentiation. BMMSCs were injected into an ischemic, viable region of the myocardium. Patients were followed for 3 years.

Results

We found significant clinical improvements in exercise time (p = 0.0016), angina class (CCS) (p < 0.0001), weekly number of angina attacks (p < 0.0001) and use of nitroglycerine from (p = 0.0017). In the Seattle Angina Questionnaire there were significant improvements in physical limitation score, angina stability score, angina frequency score and quality of life score (all p < 0.0001). When comparing all hospital admissions from 3 years before to 3 years after treatment, we observed highly reduced admission rates for stable angina (p < 0.0001), revascularization (p = 0.003) and overall cardiovascular disease (p < 0.0001). No early or late side-effects of the treatment were observed.

Conclusions

The final 3-year follow-up data after intramyocardial injection of autologous BMMSCs, in patients with severe CAD and refractory angina, demonstrated sustained clinical effects, reduced hospital admissions for cardiovascular disease and excellent long-term safety. The results indicate that autotransplantation of BMMSCs to the heart does not only improve symptoms but also slows down disease progression.     

The Use of Condensational Growth Methods for Efficient Drug Delivery to the Lungs during Noninvasive Ventilation High Flow Therapy

Purpose

The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques.

Methods

An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations.

Results

Significant improvement in the lung dose (3–4× increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5 μm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results.

Conclusions

These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.     

Photo‐Fries Rearrangement in Polymeric Media: An Investigation on Fully Aromatic Esters Containing the Naphthyl Chromophore

The present paper deals with the photo‐Fries rearrangement of fully aromatic esters in polymeric media. Low molecular weight aryl esters bearing the 1‐naphthyl chromophore were investigated with respect to their photochemical reactivity and the yield of hydroxyketones as the photo‐Fries rearrangement product. In particular, the phenyl, 4‐methylphenyl and 1‐naphthyl ester of 1‐naphthoic acid, as well as benzoic acid, 1‐naphthyl ester were dissolved in a polysiloxane matrix and exposed to 313 nm UV light. The progress of the photoreaction was assessed by quantitative FT‐IR spectroscopy. Both 1‐naphthoic acid, phenyl ester and benzoic acid, 1‐naphthyl ester underwent the photoreaction upon 313 nm irradiation. This indicates that in these fully aromatic esters, the initial C? O bond scission also occurs upon selective photoexcitation of the acyl unit in the molecule. It was found that phenyl and 4‐methylphenyl esters of 1‐naphthoic acid gave the highest yields of hydroxyketone when irradiated in polymer matrix. Based upon these results, a photoreactive monomer was designed which contains naphthoic acid, phenyl ester units attached to a norbornene ring. This monomer was then polymerized by ring opening metathesis polymerization (ROMP). The polymer showed a high yield in the photo‐Fries reaction upon 313 nm illumination. Moreover, a large increase in the refractive index (Δn up to +0.043 at λ = 370 nm) was observed which makes this polymer interesting for optical applications (e.g., waveguiding and diffractive optics).

     

Enhancements to nutrition program in Indian integrated child development services increased growth and energy intake of children

The Indian Integrated Child Development Services (ICDS) provides supplemental food to children aged 6 mo to 6 y. This study assessed the impact of enhancements to the existing Supplemental Nutrition Program of local production of supplemental food, home fortification with a micronutrient powder, and improved program monitoring. A quasi-experimental longitudinal design was used. Data were collected from 15 Anganwadi centers randomly selected from the enhanced program and 15 from the usual program. Multilevel linear regression was used to examine changes over time between the 2 groups accounting for village-level variation in intent-to-treat analysis. Children in the enhanced program initially aged 12-18 mo gained 0.72 (P = 0.02) greater height-for-age Z-score. Significant differences were observed in gain in weight-for-age Z-score among those initially aged 9-11 (2.48; P = 0.01), 12-18 (0.76; P = 0.01), and 19-24 mo old (0.73; P = 0.01), and gain in weight-for-height Z-score among 9-11 (2.66; P = 0.04) and 19-24 mo old (0.99; P = 0.01). For these age groups, the prevalence of stunting, underweight, or wasting averted ranged from 20.3 to 33.4%. Energy intake in the enhanced program was significantly greater for boys initially aged 12-18 mo (575.1 kJ/d; P = 0.03). Results from a qualitative substudy supported the plausibility of observed outcomes. ICDS would be more effective in improving child nutrition if it included these enhancements. The enhancements studied may be useful in improving program delivery and uptake of other similar programs.     

Huge myxoid liposarcoma of the esophagus: a case report

Although esophageal liposarcoma is an extremely rare tumor, liposarcoma is the most common soft tissue sarcoma in adults. Liposarcoma is currently classified into the types of well-differentiated, myxoid, round cell, pleomorphic and dedifferentiated liposarcoma. Up to now only a few cases of esophagus liposarcoma have been described in the world literature. We describe a myxoid type liposarcoma of the esophagus in a 68 year old man presented with hoarseness and intermittent dysphagea to solid food. He had a huge mass in his mouth which was mobile with gag reflex. A barium swallow, esophageal manometery and CT scan of the esophagus have not clearly revealed the mass. After endoscopic surgical resection of the tumor the histological examination revealed a myxoid liposarcoma. Both the presenting signs and symptoms and the histology type are rare for such tumor. This case demonstrate a rare differential diagnosis of intermittent dysphagia as early diagnosis is so important in those tumors and should kept in mind them, although they are quite rare.