Glucocorticoids induce retinal toxicity through mechanisms mainly associated with paraptosis.

PURPOSE: Corticosteroids have recorded beneficial clinical effects and are widely used in medicine. In ophthalmology, besides their treatment benefits, side effects, including ocular toxicity have been observed especially when intraocular delivery is used. The mechanism of these toxic events remains, however, poorly understood. In our present study, we investigated the mechanisms and potential pathways of corticosteroid-induced retinal cell death. METHODS: Rats were sacrificed 24 h and 8 days after an intravitreous injection of 1 microl (40 microg) of Kenacort Retard. The eyes were processed for ultra structure analysis and detection of activated caspase-3, cytochrome-C, apoptosis-inducing factor (AIF), LEI-L-Dnase II, terminal transferase dUTP nick end labeling (TUNEL), and microtubule-associated protein 1-light chain 3 (MAP-LC3). In vitro, rat retinal pigment epithelial cells (RPE), retinal Müller glial cells (RMG) and human ARPE-19 cells were treated with triamcinolone acetonide (TA) or other glucocorticoids. Cell viability was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5 phenyltetrazolium bromide test (MTT) assay and cell counts. Nuclei staining, TUNEL assay, annexin-V binding, activated caspase-3 and lactate dehydrogenase (LDH) production characterized cell death. Localization of cytochrome-C, AIF, LEI-and L-Dnase II, and staining with MAP-LC3 or monodansylcadaverine were also carried out. Finally, ARPE-19 cells transfected with AIP-1/Alix were exposed to TA. RESULTS: In vitro incubation of retinal cell in the presence of corticosteroids induced a specific and dose-dependent reduction of cell viability. These toxic events were not associated with the anti-inflammatory activity of these compounds but depended on the hydro solubility of their formulation. Before cell death, extensive cytoplasmic vacuolization was observed in the retinal pigment epithelial (RPE) cells in vivo and in vitro. The cells however, did not show known caspase-dependent or caspase-independent apoptotic reactions. These intracellular vacuoles were negative for MAP-LC3 but some stained positive for monodansylcadaverine. Furthermore, over expression of AIP-1/Alix inhibited RPE cell death. CONCLUSIONS: These observations suggest that corticosteroid-induced retinal cell death may be carried out mainly through a paraptosis pathway.

Neither Bad Apple nor Bad Barrel: How the Societal Context Impacts Unethical Behavior in Organizations

Every time another corporate scandal captures media headlines, the 'bad apple vs. bad barrel' discussion starts anew. Yet this debate overlooks the influence of the broader societal context on organizational behavior. In this article, we argue that misbehaviors of organizations (the 'barrels') and their members (the 'apples') cannot be addressed properly without a clear understanding of their broader context (the 'larder'). Whereas previously, a strong societal framework dampened the practical application of the Homo economicus concept (business actors as perfectly rational and egocentric utility-maximizing agents without any moral concern), specialization, individualization and globalization led to a business world disembedded from broader societal norms. This emancipated business world promotes a literal interpretation of Homo economicus among business organizations and their members. Consequently, we argue that the first step toward 'healthier' apples and barrels is to sanitize the larder, that is, adapt the framework in which organizations and their members evolve.Chaque fois qu'un nouveau scandale fait la une des médias, la question de savoir si le problème se situe au niveau des individus (des 'pommes isolées') ou au niveau des organisations (les 'caisses de pommes') refait surface. Ce débat tend néanmoins à sous-estimer l'influence du contexte sociétal plus large sur le comportement dans les organisations. Dans cet article, nous soutenons l'idée que les scandales éthiques dans les organisations ou parmi leurs membres ne peuvent être compris correctement sans une vision plus précise de leur contexte plus large (la 'cave à pommes'). Si dans le passé un contexte sociétal fort permettait d'adoucir les applications pratiques de l'Homo economicus (qui considère l'acteur économique comme un agent parfaitement rationnel et égocentrique cherchant à maximiser son utilité sans réflexion morale), l'individualisation et la globalisation ont conduit à un monde économique désencastré et déconnecté des normes sociales plus larges. Ce monde économique autonome promouvoit une interprétation littérale de l'Homo economicus parmi les entreprises et leurs employés. Il en résulte que le premier pas vers des pommes moins pourries passe par un assainissement de la cave, c'est-à-dire l'adoption d'un cadre socio-normatif qui permet un recadrage du contexte dans lequel les organisations économiques et leurs acteurs agissent.

Studies on populations of Lutzomyia longipalpis (Lutz & Neiva, 1912) (Diptera: Psychodidae: Phlebotominae) in Brazil

Studies were performed on five Brazilian populations of Lutzomyia longipalpis: Salvaterra (PA), São José do Ribamar (MA), Canindé (CE), Natal (RN) and Gruta da Lapinha, Lagoa Santa (MG). No morphological differences were observed that could distinguish between these populations. Homogeneity tests showed that the allopatric populations display a certain heterogeneity and that the sympatric populations, with different patterns of spots, are homogeneous. The Student-Newman-Keuls test, represented by Euler-Venn diagrams, showed a disjunction between the populations from the north/northeast and the one from Gruta da Lapinha. Genetic distances between the four populations (excluding the Canindé population) were within the range of intrapopulational differences. The Gruta da Lapinha population displayed a heterozygotic deficiency that could be a consequence of high levels of inbreeding due to cryptic habits of living in a small cave. These results do not favor the hypothesis of a L. longipalpis species complex in Brazil, and the species should be considered high polymorphic.

Phlebotomine sand flies in the State of Piauí, Brazil (Diptera: Psychodidae: Phlebotominae)

In 1997, 1998 and 1999 we performed several captures in the State of Piauí, in the counties of Barro Duro, Campo Maior, Castelo, Floriano, Picos, São Raimundo Nonato and Teresina. We used CDC light traps inside houses, in a primary forest and in one cave. Seventeen species were collected being Lutzomyia longipalpis, Lutzomyia samueli, Lutzomyia whitmani andLutzomyia lenti the most captured species. The genus Brumptomyia, L. whitmani, Lutzomyia sordellii, Lutzomyia carmelinoi, Lutzomyia termitophila, Lutzomyia peresi and Lutzomyia quinquefer are reported for first time in Piauí. We call the attention for the presence of L. whitmani and L. longipalpis, important vectors of leishmaniasis in various regions of South America.

The naturally occurring food mycotoxin fumonisin B1 impairs myelin formation in aggregating brain cell culture.

The effects of subchronical applications of the mycotoxin Fumonisin B1 (FB1) were analyzed in vitro, using aggregating cell cultures of fetal rat telencephalon as a model. As cells in the aggregates developed from an immature state to a highly differentiated state, with synapse and compact myelin formation, it was possible to study the effects of FB1 at different developmental stages. The results showed that FB1 did not cause cell loss and it had no effects on neurons. However it decreased strongly the total content of myelin basic protein, the main constituent of the myelin sheath, during the myelination period (DIV 18-28). The loss of myelin was not accompanied by a loss of oligodendrocytes, the myelinating cells. However FB1 had effects on the maturation of oligodendrocytes, as revealed by a decrease in the expression of galactocerebroside, and on the compaction of myelin, as shown by a reduction of the expression of the mnyelin/oligodendrocyte glycoprotein MOG. The content of the cytoskeletal component glial fibrillary acidic protein (GFAP) was decreased in differentiated astrocytes, exclusively, while neurons were not affected by 40 microM of FB1 applied continuously for 10 days. In summary, FB1 selectively affected glial cells. In particular, FB1 delayed oligodendrocyte development and impaired myelin formation and deposition.

Toxocara canis (Werner, 1782) eggs in the Pleistocene site of Menez-Dregan, France (300,000-500,000 years before present)

On the archaeological site of Menez-Dregan in Brittany, France, dated 300,000-500,000 years-old, paleoparasitological analysis of cave deposits led to the detection of well-preserved helminth eggs, which morphology and morphometry pointed to the diagnosis of Toxocara canis eggs, a parasite of carnivore mammals. Paleolithic remains suggested a parasitism of the hyena Crocuta spelaea or other canids that inhabited the region.

Standard Evaluation Framework (SEF) for weight management interventions Presentation

This presentation summaries the Standard Evaluation Framework which is designed to support high quality, consistent evaluation of weight management interventions in order to increase the evidence base.

Audio as medium for content distribution (providing access to knowledge)

Reaching and educating the masses to the benefit of all of mankind is the ultimate goal and through the use of this technology facility/tool many can be reached in their own language, in their own community, in their own time and at their own pace. Making this content available to those who will benefit from the information, is vital. These people who want to consume the content are not necessarily that interested in the qualification, they need the information. Making the content available in an auditory format may also help those who may not be as literate as others. The uses of audio/ recorded lessons have a number of uses and should not just be seen as a medium for content distribution to distant communities. Recording lectures makes it possible for a lecturer to present lectures to a vast number of students, while just presenting the lecture once.

Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study.

Objective To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study. Design Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Participants 109 118 men and 254 870 women, mainly aged 37-70. Main outcome measures Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcohol consumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer. Results If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (−3 to 38%) for liver, 17% (10 to 25%) and 4% (−1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33 037 of 178 578 alcohol related cancer cases in men and 17 470 of 397 043 alcohol related cases in women. Conclusions In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.

The INSIG2 rs7566605 polymorphism is not associated with body mass index and breast cancer risk

Background The single nucleotide polymorphism rs7566605, located in the promoter of the INSIG2 gene, has been the subject of a strong scientific effort aimed to elucidate its possible association with body mass index (BMI). The first report showing that rs7566605 could be associated with body fatness was a genome-wide association study (GWAS) which used BMI as the primary phenotype. Many follow-up studies sought to validate the association of rs7566605 with various markers of obesity, with several publications reporting inconsistent findings. BMI is considered to be one of the measures of choice to evaluate body fatness and there is evidence that body fatness is related with an increased risk of breast cancer (BC). Methods we tested in a large-scale association study (3,973 women, including 1,269 invasive BC cases and 2,194 controls), nested within the EPIC cohort, the involvement of rs7566605 as predictor of BMI and BC risk. Results and Conclusions In this study we were not able to find any statistically significant association between this SNP and BMI, nor did we find any significant association between the SNP and an increased risk of breast cancer overall and by subgroups of age, or menopausal status.

Demyelination induced by protein kinase C-activating tumor promoters in aggregating brain cell cultures.

The plasticity of mature oligodendrocytes was studied in aggregating brain cell cultures at the period of maximal expression of myelin marker proteins. The protein kinase C (PKC)-activating tumor promoters mezerein and phorbol 12-myristate 13-acetate (PMA), but not the inactive phorbol ester analog 4alpha-PMA, caused a pronounced decrease of myelin basic protein (MBP) content and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity. In contrast, myelin/oligodendrocyte protein (MOG) content was affected relatively little. Northern blot analyses showed a rapid reduction of MBP and PLP gene expression induced by mezerein, and both morphological and biochemical findings indicate a drastic loss of compact myelin. During the acute phase of demyelination, only a relatively small increase in cell death was perceptible by in situ end labeling and in situ nick translation. Basic fibroblast growth factor (bFGF) also reduced the levels of the oligodendroglial differentiation markers and enhanced the demyelinating effects of the tumor promoters. The present results suggest that PKC activation resulted in severe demyelination and partial loss of the oligodendrocyte-differentiated phenotype.

Assay for high glucose-mediated islet cell sensitization to apoptosis induced by streptozotocin and cytokines

Pancreatic beta-cell apoptosis is known to participate in the beta-cell destruction process that occurs in diabetes. It has been described that high glucose level induces a hyperfunctional status which could provoke apoptosis. This phenomenon is known as glucotoxicity and has been proposed that it can play a role in type 1 diabetes mellitus pathogenesis. In this study we develop an experimental design to sensitize pancreatic islet cells by high glucose to streptozotocin (STZ) and proinflammatory cytokines [interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma]-induced apoptosis. This method is appropriate for subsequent quantification of apoptotic islet cells stained with Tdt-mediated dUTP Nick-End Labeling (TUNEL) and protein expression assays by Western Blotting (WB).

Diversity of sandflies (Psychodidae: Phlebotominae) captured in sandstone caves from Central Amazonia, Brazil

In the present paper we describe the diversity of phlebotomine sandflies collected in three sandstone caves in the municipality of Presidente Figueiredo, state of Amazonas, Brazil. The phlebotomines were captured during 2006 with CDC light traps. Guano samples from inside the Gruta Refúgio do Maruaga were collected to investigate the presence of immature specimens. A total of 2,160 adult phlebotomines representing 15 species were captured. Pintomyia pacae was the dominant species in Gruta dos Animais (1,723 specimens) and Gruta dos Lages (50 specimens) and Deanemyia maruaga new comb (280 specimens) was the dominant species in Gruta Refúgio do Maruaga. A total of 18 guano samples were collected and seven of these samples included immature specimens. A total of 507 immature specimens were captured; 495 of these specimens were larvae and 12 were pupae. The presence of paca (Agouti paca) footprints near Gruta dos Animais and Gruta dos Lages suggests the association of Pi. pacae with this rodent. This finding may explain the abundance of Pi. pacae in these locations, while the species is relatively rare in the forest. Deanemyia maruaga is a cave species that uses guano to breed during its immature stages. Adult specimens of this species are apparently parthenogenetic and autogenous and represent the second record of parthenogenesis for the subfamily Phlebotominae.

Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study.

INTRODUCTION Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. METHODS Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. RESULTS For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. CONCLUSIONS An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.