Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung

Rationale: The molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown. Objective: To determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats. Methods: Seven-day old rats were ventilated with room air for 8, 12 and 24 h using relatively moderate tidal volumes (8.5 mL.kg-1). Measurement and Main Results: Ventilation for 24 h (h) decreased the number of elastin-positive secondary crests and increased the mean linear intercept, indicating arrest of alveolar development. Proliferation (assessed by BrdU incorporation) was halved after 12 h of ventilation and completely arrested after 24 h. Cyclin D1 and E1 mRNA and protein levels were decreased after 8-24 h of ventilation, while that of p27Kip1 was significantly increased. Mechanical ventilation for 24 h also increased levels of p57Kip2, decreased that of p16INK4a, while the levels of p21Waf/Cip1 and p15INK4b were unchanged. Increased p27Ki

Sox17 Promotes Cell Cycle Progression and Inhibits TGF-β/Smad3 Signaling to Initiate Progenitor Cell Behavior in the Respiratory Epithelium

The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-β)-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-β1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells

Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells

Inflammation has long been implicated as a contributor to pathogenesis in many CNS illnesses, including Lyme neuroborreliosis. Borrelia burgdorferi is the spirochete that causes Lyme disease and it is known to potently induce the production of inflammatory mediators in a variety of cells. In experiments where B. burgdorferi was co-cultured in vitro with primary microglia, we observed robust expression and release of IL-6 and IL-8, CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES), but we detected no induction of microglial apoptosis. In contrast, SH-SY5Y (SY) neuroblastoma cells co-cultured with B. burgdorferi expressed negligible amounts of inflammatory mediators and also remained resistant to apoptosis. When SY cells were co-cultured with microglia and B. burgdorferi, significant neuronal apoptosis consistently occurred. Confocal microscopy imaging of these cell cultures stained for apoptosis and with cell type-specific markers confirmed that it was predominantly the SY cells that were dying. Microarray analysis demonstrated an intense microglia-mediated inflammatory response to B. burgdorferi including up-regulation in gene transcripts for TLR-2 and NFκβ. Surprisingly, a pathway that exhibited profound changes in regard to inflammatory signaling was triggering receptor expressed on myeloid cells-1 (TREM1). Significant transcript alterations in essential p53 pathway genes also occurred in SY cells cultured in the presence of microglia and B. burgdorferi, which indicated a shift from cell survival to preparation for apoptosis when compared to SY cells cultured in the presence of B. burgdorferi alone. Taken together, these findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect. If, as we hypothesized, neuronal apoptosis is the key pathogenic event in Lyme neuroborreliosis, then targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Trends in fishery resource utilisation on the Great Fish Estuary

Potts, W.M., Cowley, P.D., Corroyer, B. & Næsje, T.F. 2005. Trends in fishery resource utilisation on the Great Fish Estuary. - NINA Report 50. 34pp. The Great Fish Estuary, located in the Eastern Cape Province, is becoming an increasingly popular fishing venue. A resource utilisation study consisting of a series of roving creel interview surveys was conducted in the estuary between March 200 I and February 2002 and between October 2003 and September 2004. During interviews with resource users, demographic informat ion as well as catch, effort, bait, duration of the fishing trip and number of rods/lines were obtained. Recreational shore fishers dominat ed during both study periods (54 %, both periods), followed by subsistence fishers (40 % - 1st st udy period, 23 % - 2nd study period) and recreat ional boat fishers (5 % - 1st study period, 23 % - 2nd st udy period). The increase in recreational boat fishers between the two study periods, was most probably attributed to the increased sampling on weekend days during the second study period and to the improved infrastructure at the Fish River Diner Caravan Park. Spotted grunter (Pomadasys commersonnii) and dusky kob (Argyrosomus japonicus) dominated the catches during both st udy periods. The overall catch per unit effort was lower during the second (0.19 fish/angler-hour) than during the first (0.22 fish/angler-hour) study period, while the distribution of fishing effort was more widespread during the second study period than in the fi rst . The total fishing effort during the second study period was twice as high (122 044 hrs), while the total catch was only o ne third higher (18 978 fish) than in the first study period (60 436 hrs and 12 752 fish, respectively). Results from the two study periods were used to make recommendations for the design of future estuarine fishery surveys. While the study showed a variety of short -term fluctuations, long term monitoring studies are recommended to examine trends in the Great Fish Estuary fisheries and other estuarine fisheries in South Africa. Subsistence fishery, recreational fishery, bait fishery, datacollection protocols, managemen

Verger Cidricole de Demain : les enseignements après 6 ans d’expérimentation système pour réduire les intrants en jeunes vergers cidricoles

International audienceThe “Verger Cidricole de Demain” (literally: Cider Apple Orchards of the Future) research project had experimented for 6 years with 9 low-input cider apple orchards named “ECO”. These were established under field conditions in 9 cider growers spread out in the north-west of France. With regard to 9 cider apple orchard references named “PROD”, the project aimed at assessing the technical feasibility and the economic, environmental, social and agronomic performances of these orchard prototypes, where cultural practices had been combined in a systemic approach. Thanks to the record of about 40,000 data points, technical and economic references had been acquired to reduce inputs in young cider apple orchards, such as the use of pesticides. The 9 ECO systems reached an average reduction of the chemical treatment frequency index (in French: IFT) of 48 % with regard to the PROD reference. When combined with changes in fertilization and plantation of flower strips in the orchard inter-rows, the alternatives to herbicide use in weed management seem to be more penalizing on the first fruiting than the reduction of fungicides and insecticides. However, thanks to the tested alternative strategies to fight apple scab, fungicide treatment frequency index was significantly reduced without impacting the yields of the ECO orchards. Viable low-input farming practices remain possible in cider apple orchards if some technics and their combinations are optimised. Among these are: genetics (varietal resistance and adapted rootstocks), prophylaxis, biocontrol products, efficiency (models and decision thresholds), physical protections (inert mulches on the tree rows for weed management, such as wood chip mulch or weed fabric, associated with an optimal fertilization), beneficial insects (by preservation with plantation of flower strips).Durant 6 ans, le programme Verger Cidricole de Demain a expérimenté 9 vergers de pommiers à cidre bas-intrants « ECO », implantés chez 9 cidriculteurs du Nord-Ouest de la France. En comparaison à 9 vergers témoin « PROD », le projet visait à évaluer la faisabilité technique et les performances économiques, environnementales, sociales et agronomiques de ces vergers prototypes, où des pratiques culturales ont été combinées dans une approche dite « système ». Grâce à l’enregistrement de près de 40 000 données, des références technico-économiques ont été acquises sur les moyens permettant de réduire les intrants en jeune verger, notamment l’emploi des produits phytosanitaires. Les 9 systèmes « ECO » ont atteint une réduction moyenne des IFT hors biocontrôle de 48%. Combinées aux changements de pratiques de fertilisation et de couverture sur l’inter-rang (implantation de bandes fleuries), les méthodes alternatives au désherbage chimique du rang testées semblent davantage pénaliser l’entrée en production des systèmes « ECO » que la réduction des fongicides et des insecticides. En revanche, les stratégies alternatives testées contre la tavelure ont permis de réduire significativement les IFT fongicides sans conséquence pour la production des vergers « ECO ». Des itinéraires techniques viables à plus bas intrants restent donc possibles en verger cidricole à conditions d’optimiser certains leviers et leur combinaison, parmi lesquels : la génétique (résistance variétale et porte-greffes adaptés), la prophylaxie, le biocontrôle, l’efficience (outils d’aide à la décision et seuils d’intervention), la protection physique (bâche tissée ou mulch de copeaux de bois sur le rang associé à une fertilisation optimale), la lutte biologique (par conservation via l’implantation de bandes fleuries)

Verger Cidricole de Demain : les enseignements après 6 ans d’expérimentation système pour réduire les intrants en jeunes vergers cidricoles

Durant 6 ans, le programme Verger Cidricole de Demain a expérimenté 9 vergers de pommiers à cidre bas-intrants « ECO », implantés chez 9 cidriculteurs du Nord-Ouest de la France. En comparaison à 9 vergers témoin « PROD », le projet visait à évaluer la faisabilité technique et les performances économiques, environnementales, sociales et agronomiques de ces vergers prototypes, où des pratiques culturales ont été combinées dans une approche dite « système ». Grâce à l’enregistrement de près de 40 000 données, des références technico-économiques ont été acquises sur les moyens permettant de réduire les intrants en jeune verger, notamment l’emploi des produits phytosanitaires. Les 9 systèmes « ECO » ont atteint une réduction moyenne des IFT hors biocontrôle de 48%. Combinées aux changements de pratiques de fertilisation et de couverture sur l’inter-rang (implantation de bandes fleuries), les méthodes alternatives au désherbage chimique du rang testées semblent davantage pénaliser l’entrée en production des systèmes « ECO » que la réduction des fongicides et des insecticides. En revanche, les stratégies alternatives testées contre la tavelure ont permis de réduire significativement les IFT fongicides sans conséquence pour la production des vergers « ECO ». Des itinéraires techniques viables à plus bas intrants restent donc possibles en verger cidricole à conditions d’optimiser certains leviers et leur combinaison, parmi lesquels : la génétique (résistance variétale et porte-greffes adaptés), la prophylaxie, le biocontrôle, l’efficience (outils d’aide à la décision et seuils d’intervention), la protection physique (bâche tissée ou mulch de copeaux de bois sur le rang associé à une fertilisation optimale), la lutte biologique (par conservation via l’implantation de bandes fleuries).The “Verger Cidricole de Demain” (literally: Cider Apple Orchards of the Future) research project had experimented for 6 years with 9 low-input cider apple orchards named “ECO”. These were established under field conditions in 9 cider growers spread out in the north-west of France. With regard to 9 cider apple orchard references named “PROD”, the project aimed at assessing the technical feasibility and the economic, environmental, social and agronomic performances of these orchard prototypes, where cultural practices had been combined in a systemic approach. Thanks to the record of about 40,000 data points, technical and economic references had been acquired to reduce inputs in young cider apple orchards, such as the use of pesticides. The 9 ECO systems reached an average reduction of the chemical treatment frequency index (in French: IFT) of 48 % with regard to the PROD reference. When combined with changes in fertilization and plantation of flower strips in the orchard inter-rows, the alternatives to herbicide use in weed management seem to be more penalizing on the first fruiting than the reduction of fungicides and insecticides. However, thanks to the tested alternative strategies to fight apple scab, fungicide treatment frequency index was significantly reduced without impacting the yields of the ECO orchards. Viable low-input farming practices remain possible in cider apple orchards if some technics and their combinations are optimised. Among these are: genetics (varietal resistance and adapted rootstocks), prophylaxis, biocontrol products, efficiency (models and decision thresholds), physical protections (inert mulches on the tree rows for weed management, such as wood chip mulch or weed fabric, associated with an optimal fertilization), beneficial insects (by preservation with plantation of flower strips)

Radionuclide spatial distribution mesurement and dose deposition for in vitro assessments of targeted alpha

CERVOXY COLLInternational audienc

Measurement of radionuclide spatial and temporal distribution and dose calculation for in vitro assessments of 212Pb-αVCAM-1 targeted alpha therapy

CERVOXYInternational audienc