The protective role of transferrin in Müller glial cells after iron-induced toxicity.

PURPOSE: Transferrin (Tf) expression is enhanced by aging and inflammation in humans. We investigated the role of transferrin in glial protection. METHODS: We generated transgenic mice (Tg) carrying the complete human transferrin gene on a C57Bl/6J genetic background. We studied human (hTf) and mouse (mTf) transferrin localization in Tg and wild-type (WT) C57Bl/6J mice using immunochemistry with specific antibodies. Müller glial (MG) cells were cultured from explants and characterized using cellular retinaldehyde binding protein (CRALBP) and vimentin antibodies. They were further subcultured for study. We incubated cells with FeCl(3)-nitrilotriacetate to test for the iron-induced stress response; viability was determined by direct counting and measurement of lactate dehydrogenase (LDH) activity. Tf expression was determined by reverse transcriptase-quantitative PCR with human- or mouse-specific probes. hTf and mTf in the medium were assayed by ELISA or radioimmunoassay (RIA), respectively. RESULTS: mTf was mainly localized in retinal pigment epithelium and ganglion cell layers in retina sections of both mouse lines. hTf was abundant in MG cells. The distribution of mTf and hTf mRNA was consistent with these findings. mTf and hTf were secreted into the medium of MG cell primary cultures. Cells from Tg mice secreted hTf at a particularly high level. However, both WT and Tg cell cultures lose their ability to secrete Tf after a few passages. Tg MG cells secreting hTf were more resistant to iron-induced stress toxicity than those no longer secreted hTf. Similarly, exogenous human apo-Tf, but not human holo-Tf, conferred resistance to iron-induced stress on MG cells from WT mice. CONCLUSIONS: hTf localization in MG cells from Tg mice was reminiscent of that reported for aged human retina and age-related macular degeneration, both conditions associated with iron deposition. The role of hTf in protection against toxicity in Tg MG cells probably involves an adaptive mechanism developed in neural retina to control iron-induced stress.

Ability of different adiposity indicators to identify children with elevated blood pressure.

OBJECTIVE: Body composition measured by dual-energy X-ray absorptiometry (DXA) is believed to be superior to crude measures such as BMI or waist circumference (WC) to assess health risks associated with adiposity in adults. We compared the ability of BMI, WC, waist-to-height ratio (WHtR), percentage body fat from skinfold thickness, and measures of total and central fat assessed by DXA to identify children with elevated blood pressure (BP). STUDY DESIGN: The QUALITY Study follows 630 Caucasian families (father, mother, and child originally aged 8-10 years). BP, height, weight, WC, and skinfold thickness were measured according to standardized protocols. Elevated BP was defined as systolic or diastolic BP at least 90th age, sex, and height-specific percentile. Total and central fat were determined with DXA. The area under the receiver operating characteristic (ROC) curve (AUC) statistic was computed from logistic models that adjusted for age, sex, height, Tanner stage, and physical activity. RESULTS: All adiposity indicators were highly correlated. WC and WHtR did not show superior ability over BMI to identify children with elevated SBP (P = 0.421 and 0.473). Measures of total and central fat from DXA did not show an improved ability over BMI or WC to identify children with elevated SBP (P = 0.325-0.662). CONCLUSION: Results support the use of BMI in clinical and public health settings, at least in this age group. As all indicators had a limited ability to identify children with elevated BP, results also support measurement of BP in all children of this age independent of a weight status.

The direct effects of tacrolimus and cyclosporin A on isolated human islets: A functional, survival and gene expression study.

The use of immunosuppressive drugs in transplanted patients is associated with the development of diabetes, possibly due to β-cell toxicity. To better understand the mechanisms leading to post-transplant diabetes, we investigated the actions of prolonged exposure of isolated human islets to therapeutical levels of tacrolimus (Tac) or cyclosporin A (CsA). Islets were isolated from the pancreas of multiorgan donors by enzymatic digestion and density gradient centrifugation. Functional, survival and molecular studies were then performed after 4 days of incubation with therapeutical concentrations of Tac or  CsA. Glucose-induced insulin secretion was significantly decreased in Tac, but not in CsA exposed islets, which was associated with a reduction of the amount of insulin granules as shown by electron microscopy. The percentage of apoptotic β-cells was higher in Tac than CsA exposed islets. Microarray experiments followed by Gene Set Enrichment Analysis revealed that gene expression was more markedly affected upon Tac treatment. In conclusion, Tac and CsA affect features of beta-cell differently, with several changes occurring at the molecular level.

Dispersal ability modulates the strength of the latitudinal richness gradient in European beetles.

Aim A debate exists as to whether present-day diversity gradients are governed by current environmental conditions or by changes in environmental conditions through time. Recent studies have shown that latitudinal richness gradients might be partially caused by incomplete post-glacial recolonization of high-latitude regions; this leads to the prediction that less mobile taxa should have steeper gradients than more mobile taxa. The aim of this study is to test this prediction. Location Europe. Methods We first assessed whether spatial turnover in species composition is a good surrogate for dispersal ability by measuring the proportion of wingless species in 19 European beetle clades and relating this value to spatial turnover (beta sim) of the clade. We then linearly regressed beta sim values of 21 taxa against the slope of their respective diversity gradients. Results A strong relationship exists between the proportion of wingless species and beta sim, and beta sim was found to be a good predictor of latitudinal richness gradients. Main conclusions Results are consistent with the prediction that poor dispersers have steeper richness gradients than good dispersers, supporting the view that current beetle diversity gradients in Europe are affected by post-glacial dispersal lags.

Homeostatic proliferation and survival of naïve and memory T cells.

The immune system relies on homeostatic mechanisms in order to adapt to the changing requirements encountered during steady-state existence and activation by antigen. For T cells, this involves maintenance of a diverse repertoire of naïve cells, rapid elimination of effector cells after pathogen clearance, and long-term survival of memory cells. The reduction of T-cell counts by either cytotoxic drugs, irradiation, or certain viruses is known to lead to lymphopenia-induced proliferation and restoration of normal T-cell levels. Such expansion is governed by the interaction of TCR with self-peptide/MHC (p/MHC) molecules plus contact with cytokines, especially IL-7. These same ligands, i.e. p/MHC molecules and IL-7, maintain naïve T lymphocytes as resting cells under steady-state T-cell-sufficient conditions. Unlike naïve cells, typical "central" memory T cells rely on a combination of IL-7 and IL-15 for their survival in interphase and for occasional cell division without requiring signals from p/MHC molecules. Other memory T-cell subsets are less quiescent and include naturally occurring activated memory-phenotype cells, memory cells generated during chronic viral infections, and effector memory cells. These subsets of activated memory cells differ from central memory T cells in their requirements for homeostatic proliferation and survival. Thus, the factors controlling T-cell homeostasis can be seen to vary considerably from one subset to another as described in detail in this review.

Pienen matkailuyrityksen yrittäjän taival : Oppiminen yrittäjyysprosessissa

Tämä tutkimus liittyy keskusteluun yrittäjyydestä, strategisesta prosessista ja kasvunmerkityksestä pienissä yrityksissä ja edelleen keskusteluun yrittäjästä oppijana, tilaisuuteen tarttujana ja toisaalta elämäntapaansa vaalivana yksilönä. Yrittäjän oppiminen on liitettävissä keskusteluun oppimisesta organisaatioissa, mikä tässä ymmärretään yrittäjän, yksilön oppimisena ja mahdollisuutena innovointiin ja uusiutumiseen yrittäjyysprosessissa. Tutkimuksen tavoitteena on etsiä yrittäjän oppimisen tapoja ja tuotoksia, roolia ja merkitystä strategisessa liiketoimintaprosessissa, jossa yrittäjän arvot ja pienen matkailu- ja perheyrityksen kulttuuri ohjaavat yrittäjän toimintatapaa. Edelleen tavoitteena on hahmottaa yrittäjän oppimisen ja kompetenssin ilmenemistä muutoksissa ja sidosryhmäsuhteissa. Työn lähestymistapa on hermeneuttinen. Yrittäjää lähestytään kokonaisvaltaisena yksilönä näkökulmasta, jossa yrittäjyyden prosessi ymmärretään inhimillisenä ja luovana toimintana sekä jatkuvana muutoksena. Yrittäjä nähdään oman prosessinsa määrittäjänä ja parhaana asiantuntijana. Empiirinen aineisto on laadullista. Vanhatyrittäjähaastatteluin vuosina 1998 - 99 kerätyt aineistot tarjosivat kokeilumahdollisuuden aineiston analysoinnin aloittamiseksi. Aineistojen kapean näkökulmanlaajentamiseksi kerättiin lisäaineisto neljältä yrittäjältä keskusteluin vuonna2003. Tämä Itä-Suomessa matkailualan yrittäjiltä kerätty uusi aineisto muodostaa tämän tutkimuksen keskeisen aineiston. Yrittäjyyden aiemmasta tutkimuksesta nousseet näkökulmat ovat suunnanneet tämän työn empiirisen aineiston tarkastelua. Tarkastelun kohteena ovat yrittäjä oppijana yrittäjyysprosessissaan ja yrittäjähistoriansa taitekohdissa sekä oppimisen näkyminen yrittäjän arvomaailmassa, matkailuyrityksen kulttuurissa ja sidosryhmäyhteistyössä. Tutkimuksen tulokset osoittavat, että yrittäjille jatkuva muutos on arkipäiväistä työtä. Yrittäjät hallitsevat omaa oppimis- ja yrittäjyysprosessiaan. He asettavat itse tavoitteensa liiketoiminnan suhteen, ymmärtävät liiketaloudellisia realiteetteja riittävästi; erityisesti riskien hallinta on ominaista yrittäjille. Yritysten menestystä osoittaa se, että niissä on pystytty kasvattamaan toimintaa määrällisten mittareiden puitteissa tai ainakin yrittäjän omiin tavoitteisiin on päästy. Yrittäjien oppimis- ja uusiutumiskykyä todistaa yritysten olemassaolo sinänsä ja jatkuva olemassaolon kamppailu vaikuttamalla sidosryhmiin. Vaikka näitä yrittäjiä ei anglosaksisen, schumpeterilaisen määrittelytavan mukaan voida määritellä käsitteellä 'entrepreneur', voidaan kuitenkin väittää, että heidät voidaan ymmärtää 'yrittäjyys' yrittäjiksi - rohkeiksi, uteliaiksi, itsenäisiksi, oppiviksi ja jatkuvasti uusiutuviksi yksilöiksi, jotka luovat jatkuvasti uutta arvoa yritystoiminnallaan. Oppiminen ilmenee prosessissa niin, että yrittäjät hakevat uutta tietoa sosiaalisesta suhdeverkostostaan, asiakkaiden käyttäytymisestä ja reaktioista sekä havainnoivatympäristöään tarkasti tehden vertailuja oman yrityksenä näkökulmasta alan muihin yrityksiin ja toimivat yhteistyössä muiden yrittäjien kanssa. He kyseenalaistavat omaa ja yrityksensä toimintaa, laativat suunnitelmia yrityksen laajentamiseksi tai toimintojen lisäämiseksi, mutta myös toiminnoista luopumiseksi. Oppiminenja uusiutuminen näkyvät visioissa, joissa yritystoimintaa varaudutaan muuttamaan siten, että se vastaa kulloisenkin tilanteen vaatimuksia Kuitenkin yrittäjät ovat ymmärrettävissä toimintaa ennakoiviksi, eivät niinkään toimintaa sopeuttaviksi yksilöiksi. Ennakointi voidaan nähdä muutosten työntövoimana, jolloin yrittäjät ovat enemmänkin yritystensä eteenpäin työntäjiä kuin yritystensä vetäjiä. Yrittäjät ovat omissa yrityksissään paras mahdollinen kyvykkyys- ja osaamisresurssi, joka näyttää siirtyvän näissä yrityksissä myös seuraavan sukupolven käyttöön käytännön esimerkkien ja hiljaisen tiedon kautta. Jokaiselle yrittäjälle on muotoutunut oma selviytymisstrategiansa tai toimintamallinsa, jossa on nähtävissä yrittäjän koko yrittäjyyden historian aikana ja yrittäjyysprosessissa tapahtuvan oppimisen muotoutuminen yrittäjän osaamiseksi. Näissä selviytymisstrategioissa on havaittavissa yrittäjän oma arvokäsitys, perheyrityksen kulttuuri, suhtautumistapa ympäristöön ja yrittäjän oma, persoonallinen toimintatapa yrittäjänä.

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

Background: During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions. Methods: Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations. Results: We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001. Conclusion: Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.

The role of smoking in changes in the survival curve: an empirical study in 10 European countries.

PURPOSE: We examined the role of smoking in the two dimensions behind the time trends in adult mortality in European countries, that is, rectangularization of the survival curve (mortality compression) and longevity extension (increase in the age-at-death). METHODS: Using data on national sex-specific populations aged 50 years and older from Denmark, Finland, France, West Germany, Italy, the Netherlands, Norway, Sweden, Switzerland, and the United Kingdom, we studied trends in life expectancy, rectangularity, and longevity from 1950 to 2009 for both all-cause and nonsmoking-related mortality and correlated them with trends in lifetime smoking prevalence. RESULTS: For all-cause mortality, rectangularization accelerated around 1980 among men in all the countries studied, and more recently among women in Denmark and the United Kingdom. Trends in lifetime smoking prevalence correlated negatively with both rectangularization and longevity extension, but more negatively with rectangularization. For nonsmoking-related mortality, rectangularization among men did not accelerate around 1980. Among women, the differences between all-cause mortality and nonsmoking-related mortality were small, but larger for rectangularization than for longevity extension. Rectangularization contributed less to the increase in life expectancy than longevity extension, especially for nonsmoking-related mortality among men. CONCLUSIONS: Smoking affects rectangularization more than longevity extension, both among men and women.

Survival of wild adults of Ceratitis capitata (Wiedemann) under natural winter conditions in north east Spain

The overwintering of the Mediterranean fruit fly (medfly), Ceratitis capitata (Wiedemann) at the northern limits of its geographic distribution is not yet well known. With the aim of estimating the survival rate of medfly adults in northeast Spain under natural winter conditions, a two-winter-season trial was carried out. A control was carried out in a climatic chamber at 25°C. The results showed that medfly adults were unable to survive the entire winter season in the Girona area. Climatic conditions, including the daily minimum temperature, daily maximum temperature and the high rainfall, appeared to be involved in adult mortality in winter.

Neuronal survival induced by neurotrophins requires calmodulin

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.

Twenty years of research into Chlamydia-like organisms: a revolution in our understanding of the biology and pathogenicity of members of the phylum Chlamydiae.

Chlamydiae are obligate intracellular bacteria that share a unique but remarkably conserved biphasic developmental cycle that relies on a eukaryotic host cell for survival. Although the phylum was originally thought to only contain one family, the Chlamydiaceae, a total of nine families are now recognized. These so-called Chlamydia-like organisms (CLOs) are also referred to as 'environmental chlamydiae', as many were initially isolated from environmental sources. However, these organisms are also emerging pathogens, as many, such as Parachlamydia sp., Simkania sp. and Waddlia sp., have been associated with human disease, and others, such as Piscichlamydia sp. and Parilichlamydia sp., have been documented in association with diseases in animals. Their strict intracellular nature and the requirement for cell culture have been a confounding factor in characterizing the biology and pathogenicity of CLOs. Nevertheless, the genomes of seven CLO species have now been sequenced, providing new information on their potential ability to adapt to a wide range of hosts. As new isolation and diagnostic methods advance, we are able to further explore the richness of this phylum with further research likely to help define the true pathogenic potential of the CLOs while also providing insight into the origins of the 'traditional' chlamydiae.

Univariate Parametric Survival Analysis using GS-distributions

The GS-distribution is a family of distributions that provide an accurate representation of any unimodal univariate continuous distribution. In this contribution we explore the utility of this family as a general model in survival analysis. We show that the survival function based on the GS-distribution is able to provide a model for univariate survival data and that appropriate estimates can be obtained. We develop some hypotheses tests that can be used for checking the underlying survival model and for comparing the survival of different groups.

Global surveillance of cancer survival 1995-2009 : analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75 000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. FUNDING: Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).