BIRO1, a cell-permeable BH3 peptide, promotes mitochondrial fragmentation and death of retinoblastoma cells.

Retinoblastoma is the most common pediatric intraocular neoplasm. While retinoblastoma development requires the inactivation of both alleles of the retinoblastoma tumor suppressor gene (RB1) in the developing retina, additional genomic changes are involved in tumor progression, which progressively lead to resistance of tumor cells to death. Therapeutics acting at very downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. The BH3-only proteins promote apoptosis by modulating the interaction between the pro- and antiapoptotic members of the BCL2 protein family, and this effect can be recapitulated by the BH3 domains. This report analyzes the effect of various BH3 peptides, corresponding to different BH3-only proteins, on two retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the photoreceptor cell line 661W. The BH3 peptide BIRO1, derived from the BCL2L11 death domain, was very effective in promoting Y79 and WERI-Rb cell death without affecting the 661W photoreceptor cells. This cell death was efficient even in absence of BAX and was shown to be caspase independent. While ROS production or AIF release was not detected from mitochondria of treated cells, BIRO1 initiated mitochondria fragmentation in a short period of time following treatment. IMPLICATIONS: The BIRO1 peptide is highly effective at killing retinoblastoma cells and has potential as a peptidomimetic.

Parents' willingness to pay for diminishing children's pain during blood sampling.

BACKGROUND: Blood sampling is a frequent medical procedure, very often considered as a stressful experience by children. Local anesthetics have been developed, but are expensive and not reimbursed by insurance companies in our country. We wanted to assess parents' willingness to pay (WTP) for this kind of drug. PATIENTS AND METHODS: Over 6 months, all parents of children presenting for general (GV) or specialized visit (SV) with blood sampling. WTP was assessed through three scenarios [avoiding blood sampling (ABS), using the drug on prescription (PD), or over the counter (OTC)], with a payment card system randomized to ascending or descending order of prices (AO or DO). RESULTS: Fifty-six responses were collected (34 GV, 22 SV, 27 AO and 29 DO), response rate 40%. Response distribution was wide, with median WTP of 40 for ABS, 25 for PD, 10 for OTC, which is close to the drug's real price. Responses were similar for GV and SV. Median WTP amounted to 0.71, 0.67, 0.20% of respondents' monthly income for the three scenarios, respectively, with a maximum at 10%. CONCLUSIONS: Assessing parents' WTP in an outpatient setting is difficult, with wide result distribution, but median WTP is close to the real drug price. This finding could be used to promote insurance coverage for this drug.

Manganese accumulation and its relation to "eucalyptus shoot blight in the Vale do Rio Doce"

Eucalyptus Shoot Blight in the Vale do Rio Doce (ESBVRD) is an anomaly that leads to reduced growth and, in more extreme cases, to death of eucalyptus plants. Initially diagnosed in plantations in the region of the Vale do Rio Doce, in the State of Minas Gerais, Brazil, this problem has also been found in plantations in other regions of the country and even in other countries. Although the symptoms of this anomaly are well-known, its causes are not yet understood. The aim of this study was to evaluate the cause-effect relationship between accumulation of manganese (Mn) in eucalyptus clones and ESBVRD. Characterization of the environment in areas of greater occurrence of this problem in regard to soil, climate and fluctuation of the water table was undertaken in eucalyptus plantations of the Celulose Nipo-brasileira S.A. (Cenibra) company in the region of the Vale do Rio Doce. Plant tissues were sampled in two situations. In the first situation, diagnosis occurred in the initial phase of the anomaly in clones with differentiated tolerance to the problem; in the second situation, diagnosis was made in a single clone, considered to be sensitive, in two time periods - in the phase with the strong presence of symptoms and in the recovery phase, in areas of occurrence and in areas of escape from the problem. The most ESBVRD-sensitive clone showed much higher (4.8 times higher) leaf Mn contents than more tolerant clones. In plants with the anomaly, Mn leaf contents were greater than 3,070 mg kg-1, much greater than the quantity found in those without the anomaly (734 mg kg-1). In the period in which the symptoms began to wane, there was a sharp decline in leaf Mn contents, from 2,194 to 847 mg kg-1. Manganese content in the above ground part and plant litter (44.4 g ha-1) in the area of occurrence of the anomaly was three times greater than that found in these same components (14.1 g ha-1) in the area of absence of the symptom. Based on the evidence found, such as the existence of environmental conditions favorable to high Mn availability to the plants in the areas of greatest incidence of ESBVRD, greater uptake of Mn in sensitive clones and in plants with symptoms, and a synchronism between the intensity of symptoms of ESBVRD and leaf Mn contents, it may be inferred that temporary excess of Mn in eucalyptus plants is closely related to ESBVRD.

Adherence to and effectiveness of highly active antiretroviral treatment for HIV infection: assessing the bidirectional relationship.

BACKGROUND: It is well established that high adherence to HIV-infected patients on highly active antiretroviral treatment (HAART) is a major determinant of virological and immunologic success. Furthermore, psychosocial research has identified a wide range of adherence factors including patients' subjective beliefs about the effectiveness of HAART. Current statistical approaches, mainly based on the separate identification either of factors associated with treatment effectiveness or of those associated with adherence, fail to properly explore the true relationship between adherence and treatment effectiveness. Adherence behavior may be influenced not only by perceived benefits-which are usually the focus of related studies-but also by objective treatment benefits reflected in biological outcomes. METHODS: Our objective was to assess the bidirectional relationship between adherence and response to treatment among patients enrolled in the ANRS CO8 APROCO-COPILOTE study. We compared a conventional statistical approach based on the separate estimations of an adherence and an effectiveness equation to an econometric approach using a 2-equation simultaneous system based on the same 2 equations. RESULTS: Our results highlight a reciprocal relationship between adherence and treatment effectiveness. After controlling for endogeneity, adherence was positively associated with treatment effectiveness. Furthermore, CD4 count gain after baseline was found to have a positive significant effect on adherence at each observation period. This immunologic parameter was not significant when the adherence equation was estimated separately. In the 2-equation model, the covariances between disturbances of both equations were found to be significant, thus confirming the statistical appropriacy of studying adherence and treatment effectiveness jointly. CONCLUSIONS: Our results, which suggest that positive biological results arising as a result of high adherence levels, in turn reinforce continued adherence and strengthen the argument that patients who do not experience rapid improvement in their immunologic and clinical statuses after HAART initiation should be prioritized when developing adherence support interventions. Furthermore, they invalidate the hypothesis that HAART leads to "false reassurance" among HIV-infected patients.

Value / personality - attitude - behavior hierarchy and its impact on individual performance in the context of market orientation

The purpose of this dissertation is to better understand how individual employees? values and personality traits influence their attitudes toward market orientation; how such attitudes impact their market-oriented behaviors; and how in turn, these behaviors lead to their superior individual performance. To investigate these relationships, an empirical study was conducted in the French speaking part of Switzerland and data were collected from a sample of service firms? employees from diverse departments and hierarchical levels. To a large extent, the results support the hypothesis of a hierarchical chain moving from value / personality to attitude to behavior to individual performance in relation to market orientation. Le sujet de cette thèse de doctorat est de mieux comprendre comment les valeurs et les traits de personnalité des employés influencent leurs attitudes envers l'orientation vers le marché ; comment ces attitudes ont un effet sur les comportements orientés vers le marché de ces employés et enfin, comment ces comportements conduisent à une meilleure performance individuelle. Afin d'étudier ces relations, une enquête a été conduite en Suisse romande et des données ont été collectées auprès d'un échantillon d'employés d'entreprises de service de différents départements et niveaux hiérarchiques. Les résultats sont concordants avec l'hypothèse d'une chaîne causale allant des valeurs / traits de personnalité aux attitudes, aux comportements et finalement à la performance individuelle dans le contexte de l'orientation vers le marché.

Transition of young people with chronic conditions: a cross-sectional study of patient perceptions before and after transfer from pediatric to adult health care.

UNLABELLED: The aim of this study was to compare perceived barriers to and the most preferred age for successful transition to adult health care between young people with chronic disorders who had not yet transferred from pediatric to adult health care (pre-transfer) and those who had already transferred (post-transfer). In a cross-sectional study, we compared 283 pre-transfer with 89 post-transfer young people, using a 28-item questionnaire that focused on perceived barriers to transition and beliefs about the most preferred age to transfer. Feeling at ease with the pediatrician was the most important barrier to successful transition in both groups, but was rated significantly higher in the pre-transfer compared to the post-transfer group (OR = 2.03, 95 %CI 1.12-3.71). Anxiety and lack of information were the next most important barriers, rated equally highly by the two groups (OR = 0.67, 95 %CI 0.35-1.28 and OR = 0.71, 95 %CI 0.36-1.38, respectively). More than 80 % of the respondents in both groups reported that 16-19 years was the most preferred age to transfer; more than half of all the respondents reported 18-19 years and older as the most preferred age. CONCLUSION: Better transition planning through the provision of regular and more detailed information about adult health-care providers and the transition process could reduce anxiety and contribute to a more positive attitude to overcome perceived barriers to transition from young people's perspective. Young people's preferences about transferring to adult health care provide a challenge to those children's hospitals that transfer to adult health care at a younger age.

Medical students' knowledge about end-of-life decision-making

The influence of medical students' knowledge concerning end-of-life care, considering ethical theories and clinical practice, remains controversial. We aimed to investigate medical students' knowledge of bioethical concepts related to moral kinds of death (euthanasia, disthanasia, and orthothanasia) and to analyze the influence of their clinical experience on practicing such approaches in a tertiary hospital in the state of São Paulo, Brazil. We interviewed 180 medical students [distributed in Group 1 (G1) - first to third- year students, and Group 2 (G2) - fourth to sixth-year students] to evaluate the influence of the course on "medical ethics" on ethical theories and clinical practice, using a closed questionnaire. The course on "medical ethics" did not distinguish the groups (P=0.704) in relation to bioethical concepts. Neologisms such as "cacothanasia" and "idiothanasia" were incorrectly viewed as bioethical concepts by 28% of the interviewees. Moreover, 45.3% of the sample considered health care professionals incapable of managing terminally ill patients, especially G2 (29%) as compared to G1 (16.5%, P=0.031). The concept of euthanasia was accepted by 41% of sample, as compared to 98.2% for orthothanasia. Among medical students that accepted ways to abbreviate life (22.9%), 30.1% belonged to G1, and only 16.1% to G2 (P=0.049). These medical students were unfamiliar with common bioethical concepts. Moreover, they considered healthcare professionals incapable of managing terminally ill patients. The ethical ideal of the "good death" reflects better acceptance of orthothanasia by medical students, suggesting a tendency to apply it in their future clinical practice.

Cellular and molecular studies of the effects of a selective COX-2 inhibitor celecoxib in the cardiac cell line H9c2 and their correlation with death mechanisms

Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model. After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.

Death anxiety and experiences of transcendence : peak experiences of skydivers

Terror Management Theory (TMT) suggests that human beings battle to protect ourselves from the potential terror resulting from the juxtaposition of our need for selfpreservation and our unique human ability to realize that we cannot avoid death. Over 150 studies have shown that when people are primed with the awareness of mortality they grasp onto their cultural world view more tenaciously than when they are primed with another unpleasant stimulus (i.e., show "cultural world view defense"). Applying the principles ofTMT, the first purpose of the present research was to examine whether the amount of peak experiences reduce the tendency to show cultural world view defense (an indicator of unconscious death fear) after a death prime. The second purpose was to examine a new model of implicit spirituality, by testing proposed relationships between implicit spirituality, peak experiences and intrinsic religiosity, and by testing whether peak experiences and/or intrinsic religiosity mediate the relationship between implicit spirituality and conscious and/or unconscious death fears. Skydivers were chosen as the primary participants for this research because of their unique characteristics in the context of TMT research. Previous research suggests that veteran skydivers have peak experiences as they skydive, and I assumed that their peak experiences would not be influenced by intrinsic religious beliefs. Novice skydivers may have their implicit spirituality brought forth because of their proximity to possible death. The willingness of both groups to place themselves close to death allowed their reactions to unconscious and conscious death fears to be assessed in a real setting. Novice skydivers' proximity to death made them an ideal group to study to see whether intrinsic religiosity mediated the relationship between their implicit spirituality and conscious and/or unconscious death fears. One hundred and twenty-five people participated in this research: 38 veteran and 46 novice skydivers, as well as 41 people who accompanied them to the drop zone. Of these, 23 veterans, 19 novices, and 22 friends returned a follow-up packet of questionnaires three weeks later. As expected, the veterans' unconscious death fear scores remained stable from pre-jump to post-jump (after the death prime), and three weeks later, whereas the novices' scores increased, but only marginally. As predicted, the novice skydivers' implicit spirituality was significantly higher than the veterans' and was negatively correlated with their conscious death fear, which was not mediated by their intrinsic religiosity. Only the novices' follow-up (trait) implicit spirituality correlated negatively with their pre-jump unconscious death fear. Among both groups of skydivers, there were significant relationships between implicit spirituality and peak experiences, and although the novices were significantly higher on peak experiences after the jump, peak experiences did not mediate the relationship between implicit spirituality and unconscious death fear for either group. In both groups follow-up intrinsic religiosity correlated with implicit spirituality. Peak experiences and intrinsic religiosity were not related with one another, suggesting that these are different ways of accessing an implicit spirituality. Results imply that implicit spirituality was brought forth (in the case of novice skydivers who were consciously close to death) and can be accessed through both peak experiences and intrinsic religiosity.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Max Weber in the thought of Edward Shils (1910–1995) and Ernest Gellner (1925–1995): the paradox of two Weberian approaches to the understanding of nations and nationalism?

This article traces the paradoxical impact of Weber's oeuvre on two major scholars of nationalism, Ernest Gellner and Edward Shils. Both these scholars died in 1995, leaving behind a rich corpus of writings on the nation and nationalism, much of which was inspired by Max Weber. The paradox is that although neither scholar accepted Weber's sceptical attitude to the concept of ‘nation’, they both used his other major concepts, such as ‘rationality’, ‘disenchantment’, ‘unintended consequences’, the ‘ethic of responsibility’ and ‘charisma’, in their very analyses of the nation and nationalism. And they both saw, each in his own way, the nation and nationalism as constitutive elements of modern societies. However, the paradox ceases being a paradox if one sees the integration, by Shils and Gellner, of concepts of the nation and of nationalism in the analysis of modernity, as a development of Weber's ideas.

Destructive behaviours and leadership: the source of the shift from a functional to dysfunctional workplace?

Destructive leadership behaviour often results in damage to the organisations that the individual is entrusted to lead. Although accurately pinpointing the type of destructive behaviour is difficult, this article seeks to offer suggestions as to why leaders spiral into such unattractive behaviour. After reviewing the literature, this paper highlights four drivers for destructive ways that people act based on detailed qualitative scenarios that involve how those who experienced such behaviour reacted and felt. The study reveals a noticeable human experience from which nobody can escape, and offers understanding of the study participants’ experiences. Out of respect to the participants, the authors keep their identity anonomous. We drew our subjects from a cross-section of organisations that function internationally within one area of the manufacturing industry. The article presents a model comprising two dimensions: 1) the leader’s attitude to the organisation he or she leads and 2) adequacy of his or her leadership capabilities. The models offer us understanding of the drivers of the destructive actions that the leader exhibits. Understanding allows us to provide managers with tactical methods to protect them against destructive behaviour and help them lessen the worst aspects of destructive behaviour in both their colleagues and themselves.

Significados e percepções de puérperas sobre as síndromes hipertensivas da gravidez e parto prematuro

Hypertensive syndromes in pregnancy (HSP) are configured as one of the major complications in the pregnancy and postpartum period and can lead premature newborn and subsequent hospitalization of the newborn to the Neonatal Intensive Care Unit (NICU). This study aimed to analyze the perceptions, meanings and feelings of mothers on the hypertensive syndromes in pregnancy and premature obstetric labor. The research was qualitative and has a theoretical methodological the Social Representations Theory(SRT) in the approach to the Central Nucleus Theory. The study included 70 women, mean age 29 years, predominantly school to high school, most of them married or in consensual union, primiparous and prevalence of cesarean delivery occurred between 32 and 37 weeks of pregnancy.The data were collected from may to december 2008 in the Maternity School Januário Cicco in Natal , and obtained through the following instruments for data collection: questionnaire including questions about socio-demographic status; the Free Words Association Test (FWAT) and and verbalized mental image construction used three stimuli: such as pregnancy with high blood pressure, preterm birth and NICU, and interview with the following guiding question: what it meant for you to have a pregnancy with high blood pressure and consequently the birth of a premature baby? Data analysis was performed using multi-method obtained from the data processing by EVOC (Ensemble Programmes Permettant L 'Analyze des Évocations) and ALCESTE (Analyse Lexicale par Contexte d'un Ensemble de Segment de Texte) and thematic analysis in categories. The results will be presented in four thematic units under the following representative universes: HSP, prematurity as a result of HSP, NICU and the social representations of mothers on the hypertensive disorder of pregnancy sequenced premature birth and hospitalization of the child in the NICU. The results obtained by multimethod analyses showed similar constructions and point to death as the central nucleus and negative aspects, coping strategies, need of care, knowledge about the disease, fragility and meanings of the NICU as peripheral elements. It is considered that the perceptions, meanings and feelings of puerperal women in relation to HSPs and to premature delivery are a negative social representation, with representational elements that may have influenced the adverse effects on the disease and its consequences. We suggest action on the peripheral elements of this representation, with adequate orientation, early diagnosis, effective conduct, receptive attitude on the part of the team, health promotion measures and effective public policies, in order to improve the care provided to puerperal women, making them feel welcome and minimizing their suffering

Behavioral evaluation during dental care in children ages 0 to 3 years

Purpose: Many studies concluded that the behavior of babies complicated dental care because of child immaturity or the difficulty of establishing acceptable communication and comprehension. Methods: The records of 696 babies were randomly selected from the baby clinic of Araçatuba in Brazil. Patient age ranged from 0 to 36 months. They were divided into 6 groups according to age: Group I-0 to 6 months; Group II-7 to 12 months; Group III-13 to 18 months; Group IV-19 to 24 months; Group V-25 to 30 months; Group VI-31 to 36 months. The behavior of the child was evaluated upon entrance in the dental office and during the first 4 clinical appointments with a clinical exam and oral physiotherapy. The baby was classified as collaborator (C) or noncollaborator (NC). Statistical analysis was performed using Pearson's chi-square method (P< .05). Results: The percentage of NC for Groups II, III, IV, and V (66%), was significantly higher than for groups I (30%) and VI (50%). Conclusions: Babies from 0 to 6 months showed a collaborative behavior; babies from 7 to 30 months showed noncollaborative behavior; and babies from 31 to 36 months showed no statistically significant difference between the percentage of C and NC.