The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

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Can programme theory be used as a 'translational tool’ to optimise health service delivery in a national early years’ initiative in Scotland: a case study

Background Theory-based evaluation (TBE) approaches are heralded as supporting formative evaluation by facilitating increased use of evaluative findings to guide programme improvement. It is essential that learning from programme implementation is better used to improve delivery and to inform other initiatives, if interventions are to be as effective as they have the potential to be. Nonetheless, few studies describe formative feedback methods, or report direct instrumental use of findings resulting from TBE. This paper uses the case of Scotland’s, National Health Service, early years’, oral health improvement initiative (Childsmile) to describe the use of TBE as a framework for providing feedback on delivery to programme staff and to assess its impact on programmatic action.<p></p> Methods In-depth, semi-structured interviews and focus groups with key stakeholders explored perceived deviations between the Childsmile programme 'as delivered’ and its Programme Theory (PT). The data was thematically analysed using constant comparative methods. Findings were shared with key programme stakeholders and discussions around likely impact and necessary actions were facilitated by the authors. Documentary review and ongoing observations of programme meetings were undertaken to assess the extent to which learning was acted upon.<p></p> Results On the whole, the activities documented in Childsmile’s PT were implemented as intended. This paper purposefully focuses on those activities where variation in delivery was evident. Differences resulted from the stage of roll-out reached and the flexibility given to individual NHS boards to tailor local implementation. Some adaptations were thought to have diverged from the central features of Childsmile’s PT, to the extent that there was a risk to achieving outcomes. The methods employed prompted national service improvement action, and proposals for local action by individual NHS boards to address this.<p></p> Conclusions The TBE approach provided a platform, to direct attention to areas of risk within a national health initiative, and to agree which intervention components were 'core’ to its hypothesised success. The study demonstrates that PT can be used as a 'translational tool’ to facilitate instrumental use of evaluative findings to optimise implementation within a complex health improvement programme.<p></p&gt

The impact of ambient temperature on mortality among the urban population in Skopje, Macedonia during the period 1996–2000

BACKGROUND: This study assesses the relationship between daily numbers of deaths and variations in ambient temperature within the city of Skopje, R. Macedonia. METHODS: The daily number of deaths from all causes, during the period 1996–2000, as well as those deaths from cardiovascular diseases, occurring within the city of Skopje were related to the average daily temperature on the same day using Multiple Regression statistical analyses. Temperature was measured within the regression model as two complementary variables: 'Warm' and 'Cold'. Excess winter mortality was calculated as winter deaths (deaths occurring in December to March) minus the average of non-winter deaths (April to July of the current year and August to November of the previous year). RESULTS: In this study the average daily total of deaths was 7% and 13% greater in the cold when compared to the whole period and warm period respectively. The same relationship was noticed for deaths caused by cardiovascular diseases. The Regression Beta Coefficient (b = -0.19) for the total mortality as a function of the temperature in Skopje during the period 1996–2000 was statistically significant with negative connotation as was the circulatory mortality due to average temperature (statistically significant regression Beta coefficient (b = -0.24)). A measure of this increase is provided, on an annual basis, in the form of the excess winter mortality figure. CONCLUSION: Mortality with in the city of Skopje displayed a marked seasonality, with peaks in the winter and relative troughs in the summer

The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time

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Взаємний зв'язок властивостей і структури плівкових чутливих елементів сенсорів магнітного поля

Дисертацію присвячено комплексним експериментальним дослідженням особливостей структурно-фазового стану та магнітних і магніторезистивних властивостей багатошарових плівкових систем на основі Co і Cu, Co і Cr, Fe і Cr та Fe і Cu як можливих матеріалів чутливих елементів сенсорів різного призначення. У роботі встановлено взаємозв’язок між товщиною магнітних шарів і немагнітних прошарків, орієнтацією зразка у зовнішньому магнітному полі, температурою термообробки та магнітними, магніторезистивними і магнітооптичними властивостями багатошарових плівкових систем із можливим спін-залежним розсіюванням електронів. Визначені величини магнітоопору, коерцитивної сили, коефіцієнта прямокутності й чутливості плівкової системи до магнітного поля досліджуваних плівкових систем як приладових структур для формування первинних перетворювачів. Установлена кореляція між структурно-фазовим станом, магнітними та магнітооптичними властивостями тришарових плівкових систем з різним типом розчинності компонент як функціональних елементів датчиків. Запропонована схематична конструкція АМР-датчика магнітного поля для тришарових плівкових систем із спін-залежним розсіюванням електронів. У результаті проведених досліджень впливу геометрії вимірювання, температури термообробки та загальної концентрації феромагнітної компоненти в системі на магнітні й магніторезистивні властивості визначені можливі області застосування плівкових систем на основі Co і Cu або Cr та Fe і Cu або Cr.Диссертация посвящена комплексным экспериментальным исследованиям особенностей структурно-фазового состояния, магнитных магниторезистивных свойств многослойных пленочных систем на основе Co и Cu, Co и Cr, Fe и Cr и Fe и Cu в качестве возможных материалов чувствительных элементов сенсоров различного назначения. В работе установлена взаимосвязь между толщиной магнитных слоев и немагнитных прослоек, ориентацией образца во внешнем магнитном поле, температурой термообработки и магнитными, магниторезистивными и магнитооптическими свойствами многослойных пленочных систем с возможным спин-зависимым рассеянием электронов. При исследовании магнитных свойств пленочных систем на основе Fe, Co, Cu или Cr получено, что для пленочных систем на основе Fe и Cu в форме кривых гистерезиса наблюдается определенный перегиб, свидетельствующий о послойном перемагничивании слоев Fe, в то время как для систем на основе Fe и Cr петля гистерезиса имеет форму, подобную однослойным пленкам Fe, что говорит о преобладании ферромагнитной связи в системе. В пленочных структурах на основе Co и Cr или Cu магнитные свойства системы главным образом определяются состоянием слоев Со, поэтому форма кривых гистерезиса для обеих систем схожа с формой кривых для однослойных пленок Со, а небольшие значения коэрцитивной силы свидетельствуют о реализации ферромагнитной связи в системе. Все четыре системы характеризуются достаточно высоким значением коэффициента прямоугольности, которое при смене ориентации образца от 0 до 90° несколько уменьшается для систем Fe/Cu/Fe и Fe/Cr/Fe и, наоборот, растет в системах на основе Co и Cr. Определены величины магнитосопротивления, коэрцитивной силы, коэффициента прямоугольности и чувствительности пленочной системы к магнитному полю исследуемых пленочных систем как приборных структур для формирования первичных преобразователей. Установлена корреляция между структурно-фазовым состоянием, магнитными и магнитооптическими свойствами трехслойных пленочных систем с разным типом растворимости компонент в качестве функциональных элементов датчиков. Предложена схематическая конструкция АМР-датчика магнитного поля для трехслойных пленочных систем со спин-зависимым рассеянием электронов. В результате проведенных исследований влияния геометрии измерения, температуры термообработки и общей концентрации ферромагнитной компоненты в системе на магниторезистивные свойства определены возможные области применения пленочных систем на основе Co и Cu или Cr и Fe и Cu или Cr.The thesіs іs dedіcаted to the complex experіmentаl reseаrch between the structurаl-phаse stаte, magnetic and magnetoresistance propertіes of multіlаyer fіlm systems bаsed on the Co аnd Cu, Co аnd Cr, Fe аnd Cr, аnd Fe аnd Cu, аs the potential mаterіаls for sensіtіve elements of sensors for dіfferent purposes. Іn thіs thesis wаs found the correlаtіon between the thіckness of the mаgnetіc аnd nonmаgnetіc lаyers, the orіentаtіon of the sаmple іn аn externаl mаgnetіc fіeld, temperаture of heаt treаtment аnd mаgnetіc, mаgnetoresіstіve аnd mаgneto-optіcаl propertіes іn multіlаyer fіlm systems wіth possіble spіn-dependent scаtterіng of electrons. The vаlues of mаgnetoresіstаnce, coercіvіty, squаreness fаctor аnd sensіtіvіty of fіlm system to a mаgnetіc fіeld in the studіed fіlm systems аs devіce structures for the formаtіon of prіmаry converters were defined. The correlаtіon between the structurаl-phаse stаte, mаgnetіc аnd mаgneto-optіcаl propertіes of three-lаyer fіlm systems wіth dіfferent types of component solubіlіty аs functіonаl elements sensors was established. The schemаtіc sturucture of АMR sensor for three-lаyer fіlm systems wіth spіn-dependent scаtterіng of electrons was purposed. The possіble аreаs of аpplіcаtіons wаs іdentіfіed on the bаsіs of studіes of the effect of geometry meаsurement temperаture heаt treаtment аnd the totаl concentrаtіon of ferromаgnetіc components іn the system on the magnetic and mаgnetoresіstіve propertіes of fіlm-systems bаsed on Co аnd Cu, or Cr аnd Fe, аnd Cu or Cr

ruvA Mutants that resolve Holliday junctions but do not reverse replication forks

RuvAB and RuvABC complexes catalyze branch migration and resolution of Holliday junctions (HJs) respectively. In addition to their action in the last steps of homologous recombination, they process HJs made by replication fork reversal, a reaction which occurs at inactivated replication forks by the annealing of blocked leading and lagging strand ends. RuvAB was recently proposed to bind replication forks and directly catalyze their conversion into HJs. We report here the isolation and characterization of two separation-of-function ruvA mutants that resolve HJs, based on their capacity to promote conjugational recombination and recombinational repair of UV and mitomycin C lesions, but have lost the capacity to reverse forks. In vivo and in vitro evidence indicate that the ruvA mutations affect DNA binding and the stimulation of RuvB helicase activity. This work shows that RuvA's actions at forks and at HJs can be genetically separated, and that RuvA mutants compromised for fork reversal remain fully capable of homologous recombination

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

Acknowledgements We thank Sian Williams of the International Primary Care Respiratory Group for her help and encouragement with the project. The OPCRD database was made available courtesy of the Respiratory Effectiveness Group and RIRL and the data were kindly prepared for analysis by Julie von Ziegenweidt. Funding The International Primary Care Respiratory Group (IPCRG) provided funding for this research project as an UNLOCK group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Database access for the OPCRD was provided by the Respiratory Effectiveness Group (REG) and Research in Real Life; the OPCRD statistical analysis was funded by REG. The Bocholtz Study was funded by PICASSO for COPD, an initiative of Boehringer Ingelheim, Pfizer and the Caphri Research Institute, Maastricht University, The Netherlands.Peer reviewedPublisher PD

Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older bio-kinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment

Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells

<p>Abstract</p> <p>Background</p> <p>Hyperactivity of the epithelial sodium (Na⁺) channel (ENaC) and increased Na⁺absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin-like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na⁺reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown.</p> <p>Methods</p> <p>We evaluated by short-circuit current (<it>I</it>_sc) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients.</p> <p>Results</p> <p>Neither hNE nor EPI-hNE4 treatments did modify <it>I</it>_scin control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased <it>I</it>_scby 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate <it>I</it>_sc, an effect which was blocked by EPI-hNE4.</p> <p>Conclusions</p> <p>These results indicate that hNE does activate ENaC and transepithelial Na⁺transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways.</p

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13–19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were ⩾16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index ⩾0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy±radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome