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No abstract given.

BACKGROUND:
Dichlorodiphenyldichloroethylene (DDE) and other organochlorines suppress immunity biomarkers in animals and humans. Our aim was to study the association between prenatal levels of DDE and lower respiratory tract infection in infants independently from polychlorinated biphenyls (PCBs) and other organochlorines.

METHODS:
Maternal levels of p'p'-DDE, dichlorodiphenyltrichloroethane (p'p-DDT), PCB congeners 28, 118, 138, 153, and 180, hexachlorobenzene, and beta-hexachlorocyclohexane were measured in first trimester serum of 584 pregnant women from a general population-based cohort in Sabadell (Catalonia, Spain). Mothers reported lower respiratory tract infection in interviewer-led questionnaires administered at infant age 6 and 14 months.

RESULTS:
Thirteen percent of babies had recurrent lower respiratory tract infection during the first 14 months of life. Among the organochlorines, DDE showed the highest levels (median = 112 ng/g lipid); dichlorodiphenyltrichloroethane was not detectable. The median total PCB level was 85 ng/g. DDE was the only organochlorine that showed an association with recurrent lower respiratory tract infection (at levels >83 ng/g, the first tertile, relative risk = 2.40 [95% confidence interval = 1.19-4.83]), lower respiratory tract infection at 6 months (1.68 [1.06-2.66]), and lower respiratory tract infection at 14 months (1.52 [1.05-2.21]). Adjusting for PCBs, hexachlorobenzene or beta-hexachlorocyclohexane did not confound the association.

CONCLUSIONS:
Immunologic suppression by DDE as observed in experimental studies could explain the relation between DDE and lower respiratory tract infection, independently of PCBs. Exposure to DDE during prenatal life could be critical for the development of the immune and respiratory systems.

BACKGROUND:
  The ratio of forced expiratory volume in 1 s and forced expiratory volume in 6 s (FEV1/FEV6) has been proposed as an alternative for FEV1/forced vital capacity (FVC) to diagnose obstructive diseases with less effort during spirometry; however, its prognostic value is unknown. We evaluated whether FEV1/FEV6 is a significant predictor of mortality in elderly subjects and compared its prognostic value with that of FEV1/FVC and FEV1.

METHODS:
  One thousand nine hundred and seventy-one subjects, aged >65 years, participated in the population-based SA.R.A. study. During the baseline exam, a multidimensional assessment included spirometry. Vital status was determined during 6 years of follow-up. Association of all-cause, cardio-pulmonary (CP) and non-CP mortality with a low FEV1/FEV6, FEV1/FVC and FEV1 was evaluated.

RESULTS:
  Among subjects with both survival data and acceptable spirometry including FEV6, all-cause unadjusted mortality rates were 7·00 and 2·46 per 100 person-years in subjects with FEV1/FEV6 less than and greater than or equal to lower limit of normal (LLN), respectively (mortality rate ratio: 2·84, 95%CI: 2·12-3·84). After adjustment for age, gender, FVC, smoke exposure and main comorbidities, the risk of all-cause mortality remained significantly increased in subjects with FEV1/FEV6
CONCLUSIONS:
  A low FEV1/FEV6 is a significant predictor of mortality in older individuals. Its prognostic value is comparable to that of a low FEV1/FVC and FEV1.

To assess household transmission of pandemic (H1N1) 2009 in San Antonio, Texas, USA, during April 15-May 8, 2009, we investigated 77 households. The index case-patient was defined as the household member with the earliest onset date of symptoms of acute respiratory infection (ARI), influenza-like illness (ILI), or laboratory-confirmed pandemic (H1N1) 2009. Median interval between illness onset in index and secondary case-patients was 4 days (range 1-9 days); the index case-patient was likely to be < or =18 years of age (p = 0.034). The secondary attack rate was 4% for pandemic (H1N1) 2009, 9% for ILI, and 13% for ARI. The secondary attack rate was highest for children <5 years of age (8%-19%) and lowest for adults > or =50 years of age (4%-12%). Early in the outbreak, household transmission primarily occurred from children to other household members and was lower than the transmission rate for seasonal influenza.

The aims of this study were to examine the phase behavior of itraconazole-phenol mixtures and assess the feasibility of topical formulations of itraconazole using eutectic mixture systems. Itraconazole-phenol eutectic mixtures were characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, and powder X-ray diffractometry. The skin permeation rates of itraconazole-phenol eutectic formulations were determined using Franz diffusion cells fitted with excised hairless mouse skins. Itraconazole can form eutectic compounds with phenol, and the hydrogen-bonding interactions between the carbonyl group in the itraconazole and hydroxyl group in phenol play a major role in itraconazole-phenol eutectic formation. Despite its high molecular weight and hydrophobicity, the drug (i.e., itraconazole) can be permeated through excised hairless mouse skins from itraconazole-phenol eutectic formulations. The findings of this study emphasize the capabilities of the topical application of itraconazole via external preparations.

BACKGROUND:
Brazil initiated universal immunization of infants with the G1P[8] human rotavirus (RV) vaccine in March 2006. This study evaluated vaccine effectiveness (VE) against severe rotavirus gastroenteritis (RVGE) hospitalizations.

METHODS:
Matched case-control study conducted at 4 hospitals in Belém from May 2008 to May 2009. Cases were children hospitalized with RVGE age-eligible to have received 2 doses of the human RV vaccine (≥ 12 weeks of age and born after March 6, 2006). For each case, 1 neighborhood and 1 hospital control without gastroenteritis was selected, matching by birth date (± 8 and ± 6 weeks, respectively). Matched odds ratio of 2-dose RV vaccination in cases versus controls was used to estimate VE (1 - odds ratio × 100%).

RESULTS:
Of 538 RVGE cases, 507 hospital controls and 346 neighborhood controls included, 54%, 61%, and 74% had received both RV vaccine doses. VE against RVGE hospitalization was 75.8% (95% confidence interval [CI]: 58.1-86.0) using neighborhood controls and 40.0% (95% CI: 14.2-58.1) using hospital controls. VE in children 3 to 11 months and ≥ 12 months of age was 95.7% (95% CI: 67.8-99.4) and 65.1% (95% CI: 37.2-80.6) using neighborhood controls, and 55.6% (95% CI: 12.3-77.5) and 32.1% (95% CI: -3.7-55.5) using hospital controls. G2P[4] accounted for 82.0% of RVGE hospitalizations. G2P[4]-specific VE was 75.4% (95% CI: 56.7-86.0) using neighborhood controls and 38.9% (95% CI: 11.1-58.0) using hospital controls.

CONCLUSIONS:
Although fully heterotypic G2P[4] was the predominant RV strain, good VE was demonstrated. VE was highest in children aged 3 to 11 months. However, protection in children ≥ 12 months of age, important for optimal public health impact, was significantly sustained based on estimates obtained using neighborhood controls.

The cortical actin cytoskeleton beneath the plasma membrane represents a physical barrier that vaccinia virus has to overcome during its exit from an infected cell. Previous observations using overexpression and pharmacological approaches suggest that vaccinia enhances its release by modulating the cortical actin cytoskeleton by inhibiting RhoA signalling using the viral protein F11. We have now examined the role of F11 and its ability to interact with RhoA to inhibit its downstream signalling in the spread of vaccinia infection both in vitro and in vivo. Live cell imaging over 48 hours reveals that loss of F11 or its ability to bind RhoA dramatically reduces the rate of cell-to-cell spread of the virus in a cell monolayer. Cells infected with the DeltaF11L virus also maintained their cell-to-cell contacts, and did not undergo virus-induced motility as observed during wild-type infections. The DeltaF11L virus is also attenuated in intranasal mouse models of infection, as it is impaired in its ability to spread from the initial sites of infection to the lungs and spleen. Loss of the ability of F11 to bind RhoA also reduces viral spread in vivo. Our results clearly establish that viral-mediated inhibition of RhoA signalling can enhance the spread of infection not only in cell monolayers, but also in vivo.

In this contribution, a pulse sequence is described for recording accordion-optimized DEPT experiments. The proposed ACCORDEPT experiment detects a wide range of one-bond coupling constants using accordion optimization. As a proof of concept, this strategy has been applied to a mesogen containing a large range of one-bond (1)J(CH) coupling constants associated with the various structural elements. The ACCORDEPT experiment afforded significant enhancements for the resonances with the larger (1)J(CH) couplings, similar SNR for aliphatic resonances, but reduced SNR for aliphatic resonances as compared with the standard DEPT experiment. In addition, the ACCORDEPT is straightforward to implement, does not require any supplementary calibration procedures and can be used under automated conditions without difficulty by inexperienced users.

No abstract given.

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 μm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

The topic of vascular anomalies is uncommon in the hand surgery literature, but hand surgeons do diagnose and treat patients with hemangiomas and vascular malformations. These are separate entities and require different treatment strategies. Proper diagnosis will lead to timely and appropriate treatment.

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Arg/Arg homozygotes for the Gly16Arg polymorphism in the β₂-adrenoreceptor gene (ADRB2) have a reduced response to short-acting β₂-agonists but no effect has been associated with long-acting β₂-agonists (LABAs). We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects. There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p = 0.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p = 0.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean ± se decrease in decline in forced expiratory volume in 1 s of 7.7 ± 2.5 mL·yr⁻¹ was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p = 0.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed β₂-adrenoreceptor desensitisation.

The aim of this study was to define the effects on antigen-presenting cells of the expression of HIV antigens from an attenuated poxvirus vector. We have analyzed the transcriptional changes in gene expression following infection of human immature monocyte-derived dendritic cells (DC) with recombinant modified vaccinia virus Ankara (MVA) expressing the genes encoding the gp120 and Gag-Pol-Nef antigens of HIV type 1 clade B (referred to as MVA-B) versus parental MVA infection. Using microarray technology and real-time reverse transcription-PCR, we demonstrated that the HIV proteins induced the expression of cytokines, cytokine receptors, chemokines, chemokine receptors, and molecules involved in antigen uptake and processing, including major histocompatibility complex (MHC) genes. Levels of mRNAs for interleukin-1, beta interferon, CCR8, and SCYA20 were higher after HIV antigen production. MVA-B infection also modulated the expression of antigen processing and presentation genes: the gene for MICA was upregulated, whereas those for HLA-DRA and HSPA5 were downregulated. Indeed, the increased expression of the gene for MICA, a glycoprotein related to major histocompatibility complex class I molecules, was shown to enhance the interaction between MVA-B-infected target cells and cytotoxic lymphocytes. The expression profiles of the genes for protein kinases such as JAK1 and IRAK2 were activated after HIV antigen expression. Several genes included in the JAK-STAT and mitogen-activated protein kinase signaling pathways were regulated after HIV antigen expression. Our findings provide the first gene signatures in DC of a candidate MVA-B vaccine expressing four HIV antigens and identified the biological roles of some of the regulatory genes, like that for MICA, which will help in the design of more effective MVA-derived vaccines.

AIMS:
Studies suggest that insulin-signaling molecules are present in the pancreatic islets. For this reason, the effects of insulin glulisine, insulin aspart and regular human insulin (RHI) on the function and molecular features of isolated human pancreatic islets were investigated.

METHODS:
Human pancreatic islets were prepared by collagenase digestion and density-gradient purification of pancreata from multiple organ donors. Islets were then cultured for 48 h in the presence of 5.5 (normal) or 22.2 (high) mmol/L of glucose with and without glulisine, aspart and RHI (10 or 100 nmol/L). Functional (glucose-stimulated insulin secretion) and molecular (quantitative RT-PCR and immunoblot) studies were performed at the end of the different incubation conditions.

RESULTS:
Glucose-stimulated insulin secretion was blunted in islets cultured in 22.2 mmol/L of glucose, with no significant effects from the exogenous added insulins. In islets maintained at 5.5 mmol/L of glucose, insulin receptor (IR) expression was reduced by low RHI, while phosphatidylinositol-3 kinase p110-alpha (PI3K) was enhanced by both concentrations of glulisine and aspart, and by high RHI. In islets preexposed to high glucose, IR expression was increased by both concentrations of aspart and RHI, but not by glulisine. Glulisine at high concentration significantly (P<0.05) increased PI3K expression. Glulisine and RHI significantly increased IRS-2 phosphorylation compared with control and aspart (P<0.05).

CONCLUSION:
Insulin analogues have differential effects on the expression of insulin-signaling molecules in human pancreatic islets that are also dependent on the degree of glucose exposure.

Nanoparticles are extensively studied for drug delivery and are proving to be effective in drug delivery and the diagnostic field. Drug delivery to lungs has its advantages over other routes of administration. Inhalable powders consisting of nanoparticles are gaining much interest in respiratory research and clinical therapy. Particle engineering technique is a key factor to develop inhalable formulations that can successfully deliver drug with improved therapeutic effect and enhanced targeting. Inhalable nanoparticles in the solid-state dry powders for targeted pulmonary delivery offer unique advantages and are an exciting new area of research. Nasal delivery of inhalable nanoparticulate powders is gaining research attention recently, particularly in vaccine applications, systemic drug delivery in the treatment of pain, and non-invasive brain targeting. Fundamental aspects and recent advancements along with future prospects of inhalable powders consisting of nanoparticles in the solid-state for respiratory delivery are presented.

Rationale: Impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. Objectives: To determine influence of PH on survival in the CF population. Methods: The UNOS database was queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mmHg and severe ≥ 35 mmHg. Measurements and Main Results: Of 2781 CF patients, 2100 were used for univariate analysis, 764 for Kaplan-Meier (KM) survival function, 687 for multivariate Cox models, and 576 (mild PH) and 132 (severe PH) for propensity score matching, respectively. Univariate analysis with KM functions found significant differences in survival for mild PH (HR = 1.747, 95% CI: 1.387, 2.201, p < 0.001) and severe PH (HR = 2.299, 95% CI: 1.639, 3.225, p < 0.001). Further assessment by multivariate Cox models identified significant risk for death for mild PH (HR = 1.757, 95% CI: 1.367, 2.258, p < 0.001) and severe PH (HR = 2.284, 95% CI: 1.596, 3.268, p < 0.001). Propensity score matching confirmed the risk for death for mild PH (HR = 1.919, 95% CI: 1.290, 2.85, p = 0.001) and severe PH (HR = 4.167, 95% CI: 1.709, 10.157, p = 0.002). Conclusions: The manifestation of PH is associated with significantly increased risk for death in CF patients with advanced lung disease.

OBJECTIVE:
We assessed whether maternal C-reactive protein (CRP) levels during pregnancy and CRP gene variations are associated with wheezing and lower respiratory tract infections (LRTIs) in offspring.

STUDY DESIGN:
Information on wheezing and LRTIs in the offspring at 6 and 14 months of age, and maternal CRP levels and genotype was obtained from a population-based birth cohort.

RESULTS:
A total of 63 children (12.5%) experienced recurrent wheezing and 61 (12.4%) a recurrent diagnosis of LRTIs. Children in the highest tertile of maternal CRP levels had a higher risk of experiencing recurrent wheezing (adjusted odds ratio, 2.87; 95% confidence interval, 1.23-6.71) and being diagnosed with recurrent LRTIs (odds ratio, 2.37; 95% confidence interval, 1.01-5.55), as compared with children in the lowest tertile. The rs1205 polymorphism influenced maternal serum CRP levels but not the risk of the offspring outcomes.

CONCLUSION:
Higher CRP levels in pregnancy are associated with wheezing and LRTIs in offspring. However, genetic variation in CRP influencing maternal levels is not related to these phenotypes.

BACKGROUND:
Although pulmonary arterial hypertension (PAH) is a potential co-morbidity in cystic fibrosis (CF), right heart catheterization (RHC) is not commonly performed in this patient population until referral for lung transplantation.

MATERIAL AND METHODS:
An non-randomized observational pilot study was performed after an exercise protocol with an upright stationary bicycle was added to RHC performed in patients with CF undergoing evaluation for lung transplantation (LT).

RESULTS:
Twelve consecutive patients with advanced lung disease due to CF referred for LT completed RHC with exercise protocol. Transthoracic echocardiography (TTE) prior to the RHC did not identify evidence of PAH or significant structural abnormalities; right and left ventricular systolic function were normal. non-randomized RHC in this same cohort found 75% (9/12) had PAH with an elevation of the mean pulmonary artery pressure (PAP) at rest with a mean (±SD) of 27.8 ± 4.9 mmHg that significantly increased during exercise to 47.2 ± 5.4 mmHg, p = 0.0025. For the last 6 patients, pulmonary vascular resistance was calculated during exercise, with a significant increase from 3.15 ± 0.3 to 12.8 ± 0.6 Wood Units (p = 0.0313) comparing measurements at rest to exercise.

CONCLUSION:
RHC at rest and during exercise was safely and effectively performed in patients with CF referred for LT. Furthermore, central hemodynamic measurements found significant worsening of PAH during exercise in a small cohort of CF patients with advanced lung disease.

Airway complications occur frequently after lung transplantation. Bronchial stenosis is the most frequently encountered complication with the most severe form of that being the vanishing bronchus intermedius syndrome (VBIS). This rare disorder has never been reported in the pediatric population. This is the first report of VBIS in a pediatric patient, specifically a 16-yr-old male patient with cystic fibrosis whose course was complicated by a lower airway infection with Aspergillus fumigatus. The VBIS responded to bronchoscopic balloon dilation and placement of an airway stent.

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