What is the potential benefit of pre-hospital extracorporeal cardiopulmonary resuscitation for patients with an out-of-hospital cardiac arrest? A predictive modelling study.

AIM: In this predictive modelling study we aimed to investigate how many patients with an out-of-hospital cardiac arrest (OHCA) would benefit from pre-hospital as opposed to in-hospital initiation of extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: A temporal spatial analysis of Utstein data was performed for all adult patients with a non-traumatic OHCA attended by three emergency medical services (EMS) covering the north of the Netherlands during a one-year period. Patients were considered potentially eligible for ECPR if they had a witnessed arrest with immediate bystander CPR, an initial shockable rhythm (or signs of life during resuscitation) and could be presented in an ECPR-centre within 45 minutes of the arrest. Endpoint of interest was defined as the hypothetical number of ECPR eligible patients after 10, 15 and 20 minutes of conventional CPR and upon (hypothetical) arrival in an ECPR-centre as a fraction of the total number of OHCA patients attended by EMS. RESULTS: During the study period 622 OHCA patients were attended, of which 200 (32%) met ECPR eligibility criteria upon EMS arrival. The optimal transition point between conventional CPR and ECPR was found to be after 15 minutes. Hypothetical intra-arrest transport of all patients in whom no return of spontaneous circulation (ROSC) was obtained after that point (n = 84) would have yielded 16/622 (2.5%) patients being potentially ECPR eligible upon hospital arrival (average low-flow time 52 minutes), whereas on-scene initiation of ECPR would have resulted in 84/622 (13.5%) potential candidates (average estimated low-flow time 24 minutes before cannulation). CONCLUSION: Even in healthcare systems with relatively short transport distances to hospital, consideration should be given to pre-hospital initiation of ECPR for OHCA as it shortens low-flow time and increases the number of potentially eligible patients.

In-Grove Spatiotemporal Spread of Citrus Huanglongbing and Its Psyllid Vector in Relation to Weather.

Reports of spatial patterns of 'Candidatus Liberibacter asiaticus'-infected asymptomatic citrus trees and 'Ca. L. asiaticus'-positive Asian citrus psyllids (ACP) are rare, as are published relationships between huanglongbing (HLB), ACP, and weather. Here, spatial patterns of 'Ca. L. asiaticus'-positive asymptomatic and symptomatic trees were determined every half year in a small grove over 2.5 years, and of HLB-symptomatic trees and ('Ca. L. asiaticus'-positive) ACP populations every month in two commercial groves for 1 year. Spread of symptomatic trees followed that of asymptomatic 'Ca. L. asiaticus'-positive trees with <6 months' delay. 'Ca. L. asiaticus'-positive asymptomatic and symptomatic fronts moved at 2.5 to 3.6 m month-1. No spatial relationship was detected between ACP populations and HLB-infected trees. HLB incidence and 'Ca. L. asiaticus'-positive ACP dynamics were tentatively positively correlated with monthly rainfall data and, to a lesser extent, with average minimum temperature.

Regional Spatial-Temporal Spread of Citrus Huanglongbing Is Affected by Rain in Florida.

Citrus huanglongbing (HLB), associated with 'Candidatus Liberibacter asiaticus' (Las), disseminated by Asian citrus psyllid (ACP), has devastated citrus in Florida since 2005. Data on HLB occurrence were stored in databases (2005 to 2012). Cumulative HLB-positive citrus blocks were subjected to kernel density analysis and kriging. Relative disease incidence per county was calculated by dividing HLB numbers by relative tree numbers and maximum incidence. Spatiotemporal HLB distributions were correlated with weather. Relative HLB incidence correlated positively with rainfall. The focus expansion rate was 1626 m month-1, similar to that in Brazil. Relative HLB incidence in counties with primarily large groves increased at a lower rate (0.24 year-1) than in counties with smaller groves in hotspot areas (0.67 year-1), confirming reports that large-scale HLB management may slow epidemic progress.

Response of consumer and research grade indoor air quality monitors to residential sources of fine particles.

The ability to inexpensively monitor PM2.5 to identify sources and enable controls would advance residential indoor air quality (IAQ) management. Consumer IAQ monitors incorporating low-cost optical particle sensors and connections with smart home platforms could provide this service if they reliably detect PM2.5 in homes. In this study, particles from typical residential sources were generated in a 120 m3 laboratory and time-concentration profiles were measured with 7 consumer monitors (2-3 units each), 2 research monitors (Thermo pDR-1500, MetOne BT-645), a Grimm Mini Wide-Range Aerosol Spectrometer (GRM), and a Tapered Element Oscillating Microbalance with Filter Dynamic Measurement System (FDMS), a Federal Equivalent Method for PM2.5 . Sources included recreational combustion (candles, cigarettes, incense), cooking activities, an unfiltered ultrasonic humidifier, and dust. FDMS measurements, filter samples, and known densities were used to adjust the GRM to obtain time-resolved mass concentrations. Data from the research monitors and 4 of the consumer monitors-AirBeam, AirVisual, Foobot, Purple Air-were time correlated and within a factor of 2 of the estimated mass concentrations for most sources. All 7 of the consumer and both research monitors substantially under-reported or missed events for which the emitted mass was comprised of particles smaller than 0.3 µm diameter.

Quantifying fine particle emission events from time-resolved measurements: Method description and application to 18 California low-income apartments.

PM2.5 exposure is associated with significant health risk. Exposures in homes derive from both outdoor and indoor sources, with emissions occurring primarily in discrete events. Data on emission event magnitudes and schedules are needed to support simulation-based studies of exposures and mitigations. This study applied an identification and characterization algorithm to quantify time-resolved PM2.5 emission events from data collected during 224 days of monitoring in 18 California apartments with low-income residents. We identified and characterized 836 distinct events with median and mean values of 12 and 30 mg emitted mass, 16 and 23 minutes emission duration, 37 and 103 mg/h emission rates, and pseudo-first-order decay rates of 1.3 and 2.0/h. Mean event-averaged concentrations calculated using the determined event characteristics agreed to within 6% of measured values for 14 of the apartments. There were variations in event schedules and emitted mass across homes, with few events overnight and most emissions occurring during late afternoons and evenings. Event characteristics were similar during weekdays and weekends. Emitted mass was positively correlated with number of residents (Spearman coefficient, ρ=.10), bedrooms (ρ=.08), house volume (ρ=.29), and indoor-outdoor CO2 difference (ρ=.27). The event schedules can be used in probabilistic modeling of PM2.5 in low-income apartments.

Effects of the Mammalian Target of Rapamycin Inhibitor Everolimus on Hepatitis C Virus Replication In Vitro and In Vivo.

BACKGROUND: The influence of immunosuppressants on hepatitis C virus (HCV) re-infection after liver transplantation, particularly mammalian target of rapamycin inhibitors, remains unclear. The aim of our study was to analyze the influence of everolimus (EVR) on HCV replication activity in the context of underlying molecular mechanisms, with focus on the pro-myelocytic leukemia protein (PML). METHODS: HCV viral load was recorded in 40 patients with post-transplant HCV re-infection before and 8 weeks after introduction of EVR. An HCV cell culture replicon system for genotype (GT) 1b, GT2b, and GT3a was used to compare the influence of EVR on HCV replication for the respective genotypes in vitro. Fluorescence-activated cell-sorting analysis was used to test for effects on cell proliferation. PML expression was silenced with the use of small hairpin RNA constructs, and PML expression was quantified by means of quantitative real-time polymerase chain reaction. RESULTS: In patients with HCV, the viral load of GT1a and GT1b was hardly affected by EVR, whereas the viral load was reduced in patients with GT2a (P ≤ .0001) or GT3 infection (P ≤ .05). In vitro EVR impairs HCV replication activity of GT2a and GT3a up to 60% (P ≤ .0005), whereas in GT1b cells, HCV replication activity is increased by 50% (P ≤ .005). Replicon cell viability was not impaired. HCV replication activity is impaired in the absence of PML, which can be reversed by overexpression of PML isoforms. Furthermore, in the absence of PML, the effect of EVR on HCV replication activity is nearly abrogated. CONCLUSIONS: The mammalian target of rapamycin inhibitor EVR influences HCV replication via PML. The herein presented results suggest a genotype-dependent benefit for an EVR-based immunosuppressive regimen in patients with GT2a or GT3 re-infection after liver transplantation.

IL-36γ is a crucial proximal component of protective type-1-mediated lung mucosal immunity in Gram-positive and -negative bacterial pneumonia.

Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in mucosal immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted immunity in IL-36γ-/- mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate mucosal immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.

Measured performance of filtration and ventilation systems for fine and ultrafine particles and ozone in an unoccupied modern California house.

This study evaluated nine ventilation and filtration systems in an unoccupied 2006 house located 250 m downwind of the I-80 freeway in Sacramento, California. Systems were evaluated for reducing indoor concentrations of outdoor particles in summer and fall/winter, ozone in summer, and particles from stir-fry cooking. Air exchange rate was measured continuously. Energy use was estimated for year-round operation in California. Exhaust ventilation without enhanced filtration provided indoor PM2.5 that was 70% lower than outdoors. Supply ventilation with MERV13 filtration provided slightly less protection, whereas supply MERV16 filtration reduced PM2.5 by 97-98% relative to outdoors. Supply filtration systems used little energy but provided no benefits for indoor-generated particles. Systems with MERV13-16 filter in the recirculating heating and cooling unit (FAU) operating continuously or 20 min/h reduced PM2.5 by 93-98%. Across all systems, removal percentages were higher for ultrafine particles and lower for black carbon, relative to PM2.5 . Indoor ozone was 3-4% of outdoors for all systems except an electronic air cleaner that produced ozone. Filtration via the FAU or portable filtration units lowered PM2.5 by 25-75% when operated over the hour following cooking. The energy for year-round operation of FAU filtration with an efficient blower motor was estimated at 600 kWh/year.

Moraxella catarrhalis induces CEACAM3-Syk-CARD9-dependent activation of human granulocytes.

The human restricted pathogen Moraxella catarrhalis is an important causal agent for exacerbations in chronic obstructive lung disease in adults. In such patients, increased numbers of granulocytes are present in the airways, which correlate with bacteria-induced exacerbations and severity of the disease. Our study investigated whether the interaction of M. catarrhalis with the human granulocyte-specific carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-3 is linked to NF-κB activation, resulting in chemokine production. Granulocytes from healthy donors and NB4 cells were infected with M. catarrhalis in the presence of different inhibitors, blocking antibodies and siRNA. The supernatants were analysed by enzyme-linked immunosorbent assay for chemokines. NF-κB activation was determined using a luciferase reporter gene assay and chromatin-immunoprecipitation. We found evidence that the specific engagement of CEACAM3 by M. catarrhalis ubiquitous surface protein A1 (UspA1) results in the activation of pro-inflammatory events, such as degranulation of neutrophils, ROS production and chemokine secretion. The interaction of UspA1 with CEACAM3 induced the activation of the NF-κB pathway via Syk and the CARD9 pathway and was dependent on the phosphorylation of the CEACAM3 ITAM-like motif. These findings suggest that the CEACAM3 signalling in neutrophils is able to specifically modulate airway inflammation caused by infection with M. catarrhalis.

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming.

Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.

Results of the California Healthy Homes Indoor Air Quality Study of 2011-2013: impact of natural gas appliances on air pollutant concentrations.

This study was conducted to assess the current impact of natural gas appliances on air quality in California homes. Data were collected via telephone interviews and measurements inside and outside of 352 homes. Passive samplers measured time-resolved CO and time-integrated NOX , NO2 , formaldehyde, and acetaldehyde over ~6-day periods in November 2011 - April 2012 and October 2012 - March 2013. The fraction of indoor NOX and NO2 attributable to indoor sources was estimated. NOX , NO2 , and highest 1-h CO were higher in homes that cooked with gas and increased with amount of gas cooking. NOX and NO2 were higher in homes with cooktop pilot burners, relative to gas cooking without pilots. Homes with a pilot burner on a floor or wall furnace had higher kitchen and bedroom NOX and NO2 compared to homes without a furnace pilot. When scaled to account for varying home size and mixing volume, indoor-attributed bedroom and kitchen NOX and kitchen NO2 were not higher in homes with wall or floor furnace pilot burners, although bedroom NO2 was higher. In homes that cooked 4 h or more with gas, self-reported use of kitchen exhaust was associated with lower NOX , NO2 , and highest 1-h CO. Gas appliances were not associated with higher concentrations of formaldehyde or acetaldehyde.

EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma.

Soft tissue sarcomas (STS) are heterogeneous malignant tumors of mesenchymal origin. Due to low incidence and high number of different histological subtypes, their pathogenesis and thus potential targets for their therapy remain barely investigated. Several studies revealed significant higher EPHB4 expression in malignancies such as prostate and colorectal cancer showing survival advantages for these tumor cells. Therefore we studied the expression of EPHB4 in a total of 46 clinical human specimens of different STS and human fibroblasts. EPHB4 mRNA and protein expression were significantly increased in synovial sarcoma. After targeting EPHB4 in fibrosarcoma, synovial sarcoma, liposarcoma and MFH sarcoma cell lines by siRNA or by inhibition of autophosphorylation using the specific EPHB4 kinase inhibitor NVP-BHG712 a decreased proliferation rate/vitality of synovial- and fibrosarcoma cells was observed. Silencing of EPHB4 significantly reduced the transmigration of synovial sarcoma cells towards fibroblasts and endothelial cells. In addition, we assessed the anti-metastatic effect of EPHB4 inhibition in vivo by intraperitoneal administration of the EPHB4 inhibitor in an appropriate sarcoma lung metastasis xenograft model. As result 43% of NVP-BHG712 treated mice (n = 3/7) developed pulmonary metastases whereas all control mice (n = 5) revealed lung metastases. The residual 57% of mice (n = 4/7) showed only small local tumor cell spots. Size measurements of the Vimentin positive area explained significant decrease in lung metastasis formation (p < 0.05) after EPHB4 kinase inhibition. In summary, these data provide first evidence of the importance of EPHB4 in the tumorigenesis of synovial sarcoma and present EPHB4 as a potential target in the therapy of this malignancy.

Formaldehyde and acetaldehyde exposure mitigation in US residences: in-home measurements of ventilation control and source control.

Measurements were taken in new US residences to assess the extent to which ventilation and source control can mitigate formaldehyde exposure. Increasing ventilation consistently lowered indoor formaldehyde concentrations. However, at a reference air exchange rate of 0.35 h(-1), increasing ventilation was up to 60% less effective than would be predicted if the emission rate were constant. This is consistent with formaldehyde emission rates decreasing as air concentrations increase, as observed in chamber studies. In contrast, measurements suggest acetaldehyde emission was independent of ventilation rate. To evaluate the effectiveness of source control, formaldehyde concentrations were measured in Leadership in Energy and Environmental Design (LEED)-certified/Indoor airPLUS homes constructed with materials certified to have low emission rates of volatile organic compounds (VOC). At a reference air exchange rate of 0.35 h(-1), and adjusting for home age, temperature and relative humidity, formaldehyde concentrations in homes built with low-VOC materials were 42% lower on average than in reference new homes with conventional building materials. Without adjustment, concentrations were 27% lower in the low-VOC homes. The mean and standard deviation of formaldehyde concentration was 33 µg/m(3) and 22 µg/m(3) for low-VOC homes and 45 µg/m(3) and 30 µg/m(3) for conventional.

Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial.

A newly developed recombinant factor IX (BAX326(1) ) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1-2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment-related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty-six bleeds (19 non-joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury-related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1-2 infusions. Longer T1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B.

Capture efficiency of cooking-related fine and ultrafine particles by residential exhaust hoods.

Effective exhaust hoods can mitigate the indoor air quality impacts of pollutant emissions from residential cooking. This study reports capture efficiencies (CE) measured for cooking-generated particles for scripted cooking procedures in a 121-m3 chamber with kitchenette. CEs also were measured for burner produced CO2 during cooking and separately for pots and pans containing water. The study used four exhaust hoods previously tested by Delp and Singer (Environ. Sci. Technol., 2012, 46, 6167-6173). For pan-frying a hamburger over medium heat on the back burner, CEs for particles were similar to those for burner produced CO2 and mostly above 80%. For stir-frying green beans in a wok (high heat, front burner), CEs for burner CO2 during cooking varied by hood and airflow: CEs were 34-38% for low (51-68 l/s) and 54-72% for high (109-138 l/s) settings. CEs for 0.3-2.0 µm particles during front burner stir-frying were 3-11% on low and 16-70% on high settings. Results indicate that CEs measured for burner CO2 are not predictive of CEs of cooking-generated particles under all conditions, but they may be suitable to identify devices with CEs above 80% both for burner combustion products and for cooking-related particles.

Inhibiting cyclin-dependent kinase 5 in the nucleus accumbens enhances the expression of amphetamine-induced locomotor conditioning.

When psychostimulant drugs like amphetamine are administered repeatedly in the presence of a contextual stimulus complex, long-lasting associations form between the unconditioned effects of the drug and the contextual stimuli. Here we assessed the role played by the proline-directed serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) in the nucleus accumbens (NAcc) on the expression of the conditioned locomotion normally observed when rats are returned to a context previously paired with amphetamine. Infusing the Cdk5 inhibitor roscovitine (40nmol/0.5µl/side) into the NAcc 30-min before the test for conditioning significantly enhanced the conditioned locomotor response observed in rats previously administered amphetamine in the test environment. This effect was specific to the expression of a conditioned response as inhibiting Cdk5 produced no effect in control rats previously administered saline or previously administered amphetamine elsewhere. As inhibiting Cdk5 during exposure to amphetamine has been found to block the accrual of locomotor conditioning, the present results suggest distinct roles for NAcc Cdk5 in the induction and expression of excitatory conditioning by amphetamine.

[New nanofibrous scaffold for corneal tissue engineering]. / Eine neue Nanofaser-Matrix für den kornealen Gewebeersatz.

BACKGROUND: An estimated 10 million people suffer worldwide from vision loss caused by corneal damage. For the worst cases, the only available treatment is transplantation with human donor corneal tissue. However, in numerous countries there is a considerable shortage of corneal tissue of good quality, leading to various efforts to develop tissue substitutes. The present study aims to introduce a nanofibrous scaffold of poly(glycerol sebacate) PGS as a biodegradable implant, for the corneal tissue engineering. MATERIALS AND METHODS: Nanofibrous scaffolds were produced from PGS and poly(ε-caprolactone) (PCL) by a modified electro-spinning process. The biocompatibility of the material was tested in vitro by colorimetric MTT assay on days 3, 5, and 7 to test the cell viability of human corneal endothelium cells (HCEC). To examine a potential immunological reaction of the scaffolds, samples were exposed to mononuclear cells derived from peripheral blood (PBMCs). After an incubation period of 3 days, supernatants were assayed for apoptotic assessment and immunogenic potentials by annexin V FITC//propidium iodide and flow-cytometric analysis. RESULTS: We could successfully demonstrate that cultivation of HCECs on PGS/PCL scaffolds was possible. Compared to day 3, cell density determined by microplate absorbance was significantly higher after 7 days of cultivation (p < 0.0001). According to the MTT data, none of the samples showed toxicity. Apoptotic assessments by FACS analysis showed that no composition stimulated apoptosis or activated PBMCs occurred. All the compositions were inert for native as well as activated T/B/NK cells and monocytes. It can be concluded that leukocytes and their activity was not affected by the scaffolds. CONCLUSION: A tissue-like scaffold mimicking the human stroma could be developed. The results indicate that PGS/PCL scaffolds could be considered as ideal candidates for corneal tissue engineering as they are biocompatible in contact to corneal endothelial cells and blood cells.

Foxp3+ regulatory T cells promote lung epithelial proliferation.

Acute respiratory distress syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3(+) regulatory T cells (Foxp3(+) T(reg) cells) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (lipopolysaccharide) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3(+) T(reg) cells in the lung during the course of resolution. To dissect the role that Foxp3(+) T(reg) cells exert on epithelial proliferation, we depleted Foxp3(+) T(reg) cells, which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3(+) T(reg) numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy, we found that Foxp3(+) T(reg) cells enhanced epithelial proliferation. Moreover, Foxp3(+) T(reg) cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3(+) T(reg) cells in repair of the lung epithelium.

Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326).

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma-derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12-65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti-FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine®) to a newly developed rFIX (Bax326(1) ) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.