РОЗРОБКА РЕГІОНАЛЬНОГО ПРОГНОЗУ ЕКОЛОГО-ЕКОНОМІЧНИХ РИЗИКІВ ПРИ ЗАКРИТТІ ШАХТ ЗАХІДНОГО ДОНБАСУ (звіт по темі ГП-412) (заключний)

Рукопис закінчено 5 грудня 2010 р. Результати роботи розглянуто науково-технічною радою, протокол № 4 від 09.12.2010 р.РЕФЕРАТ Звіт про НДР: 98 c, 27 рис., 9 табл., 29 джерело, 3 додатки. Об’єкт дослідження – процес аналізу та прогнозування еколого-економічних ризиків, які викликані гірничовидобувними роботами. Мета проекту – розробка методики регіонального прогнозу еколого-економічних ризиків, можливість виникнення яких зумовлена техногенним впливом вугільних шахт, що функціонують або закриваються. Мета етапу – апробація розробленої методики регіонального прогнозу еколого-економічних ризиків з урахуванням взаємного впливу шахтних ком-плексів Західного Донбасу, що працюють та закриваються. На основі результатів проведення експериментального моделювання еколого-економічного ризику для шахт родовища Західного Донбасу та аналізу розроблених моделей еколого-економічних ризиків отримано якісні й кількісні показники, які дали можливість розробити набор керуючих заходів для мінімізації наслідків функціонування або закриття шахтних комплексів

the effect of baby swimming with and without use of lotion on the skin barrier of infants aged 3-6 months

Hintergrund Eine adäquate Hautpflege ist besonders im Säuglingsalter wichtig, da die Hautbarrierefunktion im Zuge der Anpassung an die extrauterine Umgebung in der Säuglingsphase und über das 1. Lebensjahr hinaus wesentliche Reifungsprozesse vollzieht. Exogene Faktoren wie Chlorwasserkontakt können die empfindliche Hautbarriere beeinflussen. Ziel dieser Studie war, die Wirkung von Babyschwimmen auf die Hautbarriere der Säuglinge mit und ohne Anwendung einer Pflegelotion mittels objektiver Messmethoden zu evaluieren. Methodik In diese monozentrische, prospektive Studie wurden 44 Säuglinge im Alter von 3 bis 6 Lebensmonaten eingeschlossen und in zwei Gruppen randomisiert. In GruppeL wurde am gesamten Körper nach dem Babyschwimmen eine Pflegelotion aufgetragen, GruppeKL erhielt keine Pflegelotion. Beide Gruppen nahmen einmal pro Woche, insgesamt viermal, an einem Babyschwimmkurs teil. Während der Studie erfolgten Messungen der hautphysiologischen Parameter transepidermaler Wasserverlust (TEWL), Stratum corneum Hydratation (SCH), Haut-pH und Hautoberflächenlipide (Sebum) sowie die Beurteilung des klinischen Hautzustandes durch den Neonatal Skin Condition Score (NSCS) an Stirn, Abdomen, Oberschenkel und Gesäß. Ergebnisse Der TEWL sank signifikant in beiden Gruppen an Stirn und Oberschenkel sowie am Abdomen in GruppeKL und Gesäß in GruppeL. Die SCH blieb während der Studie in beiden Gruppen an Abdomen und Oberschenkel sowie zusätzlich an der Stirn in GruppeL stabil. Der Haut-pH blieb in beiden Gruppen an Stirn und Abdomen sowie in GruppeL an allen Körperregionen stabil. Im Bereich einer Windeldermatitis wurden tendenziell höhere pH-Werte gemessen. Das Sebum blieb in beiden Gruppen an Abdomen und Gesäß sowie in GruppeL an allen Körperregionen stabil. Der Verlauf der Hautfunktionsparameter wies geschlechtsspezifische Unterschiede auf. Jungen der GruppeL hatten einen größeren TEWL-Abfall und an der Stirn höhere Sebumwerte als Mädchen. In GruppeL wurden weniger unerwünschte Ereignisse beobachtet. Ein NSCS von 4 bis 5 kam bei einer Wasserhärte ≥ 18 °dH nach dem ersten Babyschwimmkurs zu 11,18 % vor. Schlussfolgerungen Die Effekte der Pflegelotion auf die Hautbarrierefunktion kann an den entsprechenden Messarealen als stabilisierender Effekt interpretiert werden, wobei Jungen unter Lotionsanwendung einen größeren TEWL-Abfall und an der Stirn einen vergleichsweise hohen Sebumgehalt aufwiesen. Der Verlauf der Hautfunktionsparameter kann zudem durch den Einfluss des Babyschwimmens und durch die physiologische Entwicklung bedingt sein. Inwieweit der Effekt auf unerwünschte Ereignisse durch die Anwendung der Pflegelotion klinisch relevant ist, sollte an größeren Kollektiven untersucht werden. Weitere Studien sind sinnvoll, um die wissenschaftliche Basis für das Verständnis der Barrierefunktion im Säuglingsalter zu erweitern und fundierte Kenntnisse über eine optimale Pflege, insbesondere unter der besonderen Beanspruchung des Babyschwimmens, zu evaluieren.Background Skin care is important especially in infancy as the skin barrier is maturating and adapting to the extrauterine environment during the first years of life. The aim of this study was to investigate the effect of baby-swimming and baby-lotion on the skin barrier function of term infants aged 3-6 months, using non-invasive methods. Methods In this monocentric, prospective study, 44 infants aged 3-6 months were included and randomized into two groups. In groupL, baby-lotion was applied after swimming on the entire body. In groupWL, no lotion was used. Both groups swam once a week, altogether four times. Throughout the study, skin barrier properties were evaluated on the forehead, abdomen, buttock and thigh by measuring transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin-pH and sebum; skin condition was assessed using the neonatal skin condition score (NSCS). Results In both groups, TEWL decreased significantly on forehead and thigh. Also, in groupWL on the abdomen and in groupL on the buttock a significant decrease of TEWL was noted. SCH remained stable in groupL on forehead, abdomen and thigh and decreased in both groups on the buttock. In groupL skin-pH remained stable on all body areas and in groupKL on forehead and abdomen. In regions with diaper dermatitis, skin-pH showed higher values. Sebum remained stable on abdomen and buttock in groupKL and on all body areas in groupL. Skin functional parameters varied depending on body area and gender. Boys in groupL showed a larger decrease of TEWL and higher sebum levels on the front. In groupL less adverse events (AE) were observed. NSCS ≥ 4 was observed in 11.18% of the infants after the first baby-swimming. Water hardness was ≥ 18°dH. Conclusion The effect of baby-lotion could be due to a stabilising effect on skin barrier function in the respective investigated areas; in addition, a higher decrease of TEWL in all tested areas and higher sebum values were found on the front of males in groupL. The course of the functional parameters can also be influenced by baby-swimming and physiological skin barrier development. A possible positive influence of baby-lotion on AEs should be confirmed in larger cohorts. Further studies are necessary to broaden the understanding of barrier function and age-adapted skin care especially during baby-swimming in infancy and childhood

Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis

Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic

Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells

Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFα and TRAIL signaling, mRNA and protein expression is increased by IFNα/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFα even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFα while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFα determines the dependency on either death receptor ligand for IFNα/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNα/Smac mimetic combination treatment is an effective strategy to induce cell death in TNFα- or TRAIL-responsive cancers

Interferons transcriptionally up-regulate MLKL expression in cancer cells

Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNγ up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNγ transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNγ-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D. Also, knockdown of the transcription factor IFN-regulatory factor 1 (IRF1) and signal transducer and activator of transcription (STAT) 1 as well as knockout of IRF1 significantly attenuate IFNγ-mediated induction of MLKL mRNA levels. Up-regulation of MLKL by IFNγ provides a valuable tool to sensitize cells towards necroptotic cell death and to overcome apoptosis resistance of cancer cells

Late Pliocene to early Pleistocene climate dynamics in western North America based on a new pollen record from paleo-Lake Idaho

Marked by the expansion of ice sheets in the high latitudes, the intensification of Northern Hemisphere glaciation across the Plio/Pleistocene transition at ~ 2.7 Ma represents a critical interval of late Neogene climate evolution. To date, the characteristics of climate change in North America during that time and its imprint on vegetation has remained poorly constrained because of the lack of continuous, highly resolved terrestrial records. We here assess the vegetation dynamics in northwestern North America during the late Pliocene and early Pleistocene (c. 2.8–2.4 Ma) based on a pollen record from a lacustrine sequence from paleo-Lake Idaho, western Snake River Plain (USA) that has been retrieved within the framework of an International Continental Drilling Program (ICDP) coring campaign. Our data indicate a sensitive response of forest ecosystems to glacial/interglacial variability paced by orbital obliquity across the study interval, and also highlight a distinct expansion of steppic elements that likely occurs during the first strong glacial of the Pleistocene, i.e. Marine Isotope Stage 100. The pollen data document a major forest biome change at ~ 2.6 Ma that is marked by the replacement of conifer-dominated forests by open mixed forests. Quantitative pollen-based climate estimates suggest that this forest reorganisation was associated with an increase in precipitation from the late Pliocene to the early Pleistocene. We attribute this shift to an enhanced moisture transport from the subarctic Pacific Ocean to North America, confirming the hypothesis that ocean-circulation changes were instrumental in the intensification of Northern Hemisphere glaciation.Deutsche Forschungsgemeinschaft (DE)Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/50110000165

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia

Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic

Evaluation of a novel three-dimensional robotic digital microscope (Aeos) in neurosurgery

Objective: Current literature debates the role of newly developed three-dimensional (3D) Exoscopes in the daily routine of neurosurgical practice. So far, only a small number of cadaver lab studies or case reports have examined the novel Aesculap Aeos Three-Dimensional Robotic Digital Microscope. This study aims to evaluate the grade of satisfaction and intraoperative handling of this novel system in neurosurgery. Methods: Nineteen neurosurgical procedures (12 cranial, 6 spinal and 1 peripheral nerve) performed over 9 weeks using the Aeos were analyzed. Ten neurosurgeons of varying levels of training were included after undergoing device instruction and training. Following every surgery, a questionnaire consisting of 43 items concerning intraoperative handling was completed. The questionnaires were analyzed using descriptive statistics. Results: No intraoperative complications occurred. Surgical satisfaction was ranked high (78.95%). In total, 84.21% evaluated surgical ergonomics as satisfactory, while 78.95% of the surgeons would like to use this system frequently. Image quality, independent working zoom function and depth of field were perceived as suboptimal by several neurosurgeons. Conclusion: The use of Aeos is feasible and safe in microsurgical procedures, and surgical satisfaction was ranked high among most neurosurgeons in our study. The system might offer advanced ergonomic conditions in comparison to conventional ocular-based microscopes