disappointing clinical results: Topics by Science.gov

Sample records for disappointing clinical results

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development

PubMed Central

Savonenko, Alena V; Melnikova, Tatiana; Hiatt, Andrew; Li, Tong; Worley, Paul F; Troncoso, Juan C; Wong, Phil C; Price, Don L

2012-01-01

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation—from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aβ immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development. PMID:21937983
Emotional Reactions to the Outcomes of Decisions: The Role of Counterfactual Thought in the Experience of Regret and Disappointment.

PubMed

Zeelenberg; van Dijk WW; van der Pligt J; Manstead; van Empelen P; Reinderman

1998-08-01

Regret and disappointment are emotions that can be experienced in response to an unfavorable outcome of a decision. Previous research suggests that both emotions are related to the process of counterfactual thinking. The present research extends this idea by combining it with ideas from regret and disappointment theory. The results show that regret is related to behavior-focused counterfactual thought in which the decision-maker's own actions are changed, whereas disappointment is related to situation-focused counterfactual thought in which aspects of the situation are changed. In Study 1 participants (N = 130) were asked to recall an autobiographical episode of either a regretful or a disappointing event. When asked to undo this event, regret participants predominantly changed their own actions, whereas disappointment participants predominantly changed aspects of the situation. In Study 2 all participants (N = 50) read a scenario in which a person experiences a negative event. Participants who were instructed to undo the event by changing the person's actions reported more regret than disappointment, while participants who were instructed to undo the event by changing aspects of the situation reported more disappointment than regret. Study 3 (N = 140) replicated the findings from Study 2 with a different scenario, and a design in which regret and disappointment were measured between rather than within subjects. In the discussion we address the relation among counterfactual thinking, attributions and affective reactions to decision outcomes, and the implications for decision research. Copyright 1998 Academic Press.
The impact of disappointment in decision making: inter-individual differences and electrical neuroimaging.

PubMed

Tzieropoulos, Hélène; de Peralta, Rolando Grave; Bossaerts, Peter; Gonzalez Andino, Sara L

2011-01-01

Disappointment, the emotion experienced when faced to reward prediction errors (RPEs), considerably impacts decision making (DM). Individuals tend to modify their behavior in an often unpredictable way just to avoid experiencing negative emotions. Despite its importance, disappointment remains much less studied than regret and its impact on upcoming decisions largely unexplored. Here, we adapted the Trust Game to effectively elicit, quantify, and isolate disappointment by relying on the formal definition provided by Bell's in economics. We evaluated the effects of experienced disappointment and elation on future cooperation and trust as well as the rationality and utility of the different behavioral and neural mechanisms used to cope with disappointment. All participants in our game trusted less and particularly expected less from unknown opponents as a result of disappointing outcomes in the previous trial but not necessarily after elation indicating that behavioral consequences of positive and negative RPEs are not the same. A large variance in the tolerance to disappointment was observed across subjects, with some participants needing only a small disappointment to impulsively bias their subsequent decisions. As revealed by high-density EEG recordings the most tolerant individuals - who thought twice before making a decision and earned more money - relied on different neural generators to contend with neutral and unexpected outcomes. This study thus provides some support to the idea that different neural systems underlie reflexive and reflective decisions within the same individuals as predicted by the dual-system theory of social judgment and DM.
The Impact of Disappointment in Decision Making: Inter-Individual Differences and Electrical Neuroimaging

PubMed Central

Tzieropoulos, Hélène; de Peralta, Rolando Grave; Bossaerts, Peter; Andino, Sara L. Gonzalez

2011-01-01

Disappointment, the emotion experienced when faced to reward prediction errors (RPEs), considerably impacts decision making (DM). Individuals tend to modify their behavior in an often unpredictable way just to avoid experiencing negative emotions. Despite its importance, disappointment remains much less studied than regret and its impact on upcoming decisions largely unexplored. Here, we adapted the Trust Game to effectively elicit, quantify, and isolate disappointment by relying on the formal definition provided by Bell's in economics. We evaluated the effects of experienced disappointment and elation on future cooperation and trust as well as the rationality and utility of the different behavioral and neural mechanisms used to cope with disappointment. All participants in our game trusted less and particularly expected less from unknown opponents as a result of disappointing outcomes in the previous trial but not necessarily after elation indicating that behavioral consequences of positive and negative RPEs are not the same. A large variance in the tolerance to disappointment was observed across subjects, with some participants needing only a small disappointment to impulsively bias their subsequent decisions. As revealed by high-density EEG recordings the most tolerant individuals – who thought twice before making a decision and earned more money – relied on different neural generators to contend with neutral and unexpected outcomes. This study thus provides some support to the idea that different neural systems underlie reflexive and reflective decisions within the same individuals as predicted by the dual-system theory of social judgment and DM. PMID:21258645
Disappointment and adherence among parents of newborns allocated to the control group: a qualitative study of a randomized clinical trial.

PubMed

Meinich Petersen, Sandra; Zoffmann, Vibeke; Kjærgaard, Jesper; Graff Stensballe, Lone; Graff Steensballe, Lone; Greisen, Gorm

2014-04-15

When a child participates in a clinical trial, informed consent has to be given by the parents. Parental motives for participation are complex, but the hope of getting a new and better treatment for the child is important. We wondered how parents react when their child is allocated to the control group of a randomized controlled trial, and how it will affect their future engagement in the trial. We included parents of newborns randomized to the control arm in the Danish Calmette study at Rigshospitalet in Copenhagen. The Calmette study is a randomized clinical trial investigating the non-specific effects of early BCG-vaccine to healthy neonates. Randomization is performed immediately after birth and parents are not blinded to the allocation. We set up a semi-structured focus group with six parents from four families. Afterwards we telephone-interviewed another 19 mothers to achieve saturation. Thematic analysis was used to identify themes across the data sets. The parents reported good understanding of the randomization process. Their most common reaction to allocation was disappointment, though relief was also seen. A model of reactions to being allocated to the control group was developed based on the participants' different positions along two continuities from 'Our participation in trial is not important' to 'Our participation in trial is important', and 'Vaccine not important to us' to 'Vaccine important to us'. Four very disappointed families had thought of getting the vaccine elsewhere, and one had actually had their child vaccinated. All parents involved in the focus group and the telephone interviews wanted to participate in the follow-ups planned for the Calmette study. This study identified an almost universal experience of disappointment among parents of newborns who were randomized to the control group, but also a broad expression of understanding and accepting the idea of randomization. The trial staff might use the model of reactions in understanding the parents' disappointment and in this way support their motives for participation. A generalized version might be applicable across randomized controlled trials at large. The Calmette study is registered in EudraCT (https://eudract.ema.europa.eu/) with trial number 2010-021979-85.
Behavioural consequences of regret and disappointment in social bargaining games.

PubMed

Martinez, Luis M F; Zeelenberg, Marcel; Rijsman, John B

2011-02-01

Previous research on the role of negative emotions in social bargaining games has focused primarily on social emotions such as anger and guilt. In this article, we provide a test for behavioural differences between two prototypical decision-related negative emotions-regret and disappointment-in one-shot social dilemma games. Three experiments with two different emotion-induction procedures (autobiographical recall and imagined scenarios) and two different games (the ultimatum game and the 10-coin give-some game) revealed that regret increased prosocial behaviour, whereas disappointment decreased prosocial behaviour. These results extend previous findings concerning differences between regret and disappointment to interdependent (social) situations. © 2010 Psychology Press, an imprint of the Taylor & Francis Group, an Informa business
Gratitude, protective buffering, and cognitive dissonance: How families respond to pediatric whole exome sequencing in the absence of actionable results.

PubMed

Werner-Lin, Allison; Zaspel, Lori; Carlson, Mae; Mueller, Rebecca; Walser, Sarah A; Desai, Ria; Bernhardt, Barbara A

2018-03-01

Clinical genome and exome sequencing (CGES) may identify variants leading to targeted management of existing conditions. Yet, CGES often fails to identify pathogenic diagnostic variants and introduces uncertainties by detecting variants of uncertain significance (VUS) and secondary findings. This study investigated how families understand findings and adjust their perspectives on CGES. As part of NIH's Clinical Sequencing Exploratory Research Consortium, children were recruited from clinics at the Children's Hospital of Pennsylvania (CHOP) and offered exome sequencing. Primary pathogenic and possibly pathogenic, and some secondary findings were returned. Investigators digitally recorded results disclosure sessions and conducted 3-month follow up interviews with 10 adolescents and a parent. An interdisciplinary team coded all transcripts. Participants were initially disappointed with findings, yet reactions evolved within disclosure sessions and at 3-month interviews toward acceptance and satisfaction. Families erroneously expected, and prepared extensively, to learn about risk for common conditions. During disclosure sessions, parents and adolescents varied in how they monitored and responded to each others reactions. Several misinterpreted, or overestimated, the utility of findings to attribute meaning and achieve closure for the CGES experience. Participants perceived testing as an opportunity to improve disease management despite results that did not introduce new treatments or diagnoses. Future research may examine whether families experience cognitive dissonance regarding discrepancies between expectations and findings, and how protective buffering minimizes the burden of disappointment on loved ones. As CGES is increasingly integrated into clinical care providers must contend with tempering family expectations and interpretations of findings while managing complex medical care. © 2018 Wiley Periodicals, Inc.
Does communicating disappointment in negotiations help or hurt? Solving an apparent inconsistency in the social-functional approach to emotions.

PubMed

Lelieveld, Gert-Jan; Van Dijk, Eric; Van Beest, Ilja; Van Kleef, Gerben A

2013-10-01

On the basis of a social-functional approach to emotion, scholars have argued that expressing disappointment in negotiations communicates weakness, which may evoke exploitation. Yet, it is also argued that communicating disappointment serves as a call for help, which may elicit generous offers. Our goal was to resolve this apparent inconsistency. We develop the argument that communicating disappointment elicits generous offers when it evokes guilt in the target, but elicits low offers when it does not. In 4 experiments using both verbal (Experiments 1-3) and nonverbal (Experiment 4) emotion manipulations, we demonstrate that the interpersonal effects of disappointment depend on (a) the opponent's group membership and (b) the type of negotiation. When the expresser was an outgroup member and in representative negotiations (i.e., when disappointment did not evoke guilt), the weakness that disappointment communicated elicited lower offers. When the expresser was an ingroup member and in individual negotiations (i.e., when disappointment did evoke guilt), the weakness that disappointment communicated elicited generous offers from participants. Thus, in contrast to the common belief that weakness is a liability in negotiations, expressing disappointment can be effective under particular circumstances. We discuss implications for theorizing about the social functions of emotions.
Disappointment expression evokes collective guilt and collective action in intergroup conflict: the moderating role of legitimacy perceptions.

PubMed

Solak, Nevin; Reifen Tagar, Michal; Cohen-Chen, Smadar; Saguy, Tamar; Halperin, Eran

2017-09-01

Research on intergroup emotions has largely focused on the experience of emotions and surprisingly little attention has been given to the expression of emotions. Drawing on the social-functional approach to emotions, we argue that in the context of intergroup conflicts, outgroup members' expression of disappointment with one's ingroup induces the complementary emotion of collective guilt and correspondingly a collective action protesting ingroup actions against the outgroup. In Study 1 conducted immediately after the 2014 Gaza war, Jewish-Israeli participants received information about outgroup's (Palestinians) expression of emotions (disappointment, fear, or none). As predicted, outgroup's expression of disappointment increased collective guilt and willingness to participate in collective action, but only among those who saw the intergroup situation as illegitimate. Moreover, collective guilt mediated the relationship between disappointment expression and collective action, moderated, again, by legitimacy perception. In Study 2, we replicated these results in the context of racial tension between Black and White Americans in the US. We discuss the theoretical and applied implications of the findings.
Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899
Cross-Cultural Differences in Children's Emotional Reactions to a Disappointing Situation

ERIC Educational Resources Information Center

Garrett-Peters, Patricia T.; Fox, Nathan A.

2007-01-01

Cross-cultural differences in emotional expressions following disappointment were examined in 59 Chinese American (CA) and 58 European American (EA) children. Children aged four or seven participated in a disappointing gift situation. Dimensions of expressive behaviors following disappointment were coded and included positive, negative, social…
Social disappointment explains chimpanzees' behaviour in the inequity aversion task.

PubMed

Engelmann, Jan M; Clift, Jeremy B; Herrmann, Esther; Tomasello, Michael

2017-08-30

Chimpanzees' refusal of less-preferred food when an experimenter has previously provided preferred food to a conspecific has been taken as evidence for a sense of fairness. Here, we present a novel hypothesis-the social disappointment hypothesis-according to which food refusals express chimpanzees' disappointment in the human experimenter for not rewarding them as well as they could have. We tested this hypothesis using a two-by-two design in which food was either distributed by an experimenter or a machine and with a partner present or absent. We found that chimpanzees were more likely to reject food when it was distributed by an experimenter rather than by a machine and that they were not more likely to do so when a partner was present. These results suggest that chimpanzees' refusal of less-preferred food stems from social disappointment in the experimenter and not from a sense of fairness. © 2017 The Author(s).
Combinations of Drugs in the Treatment of Obesity

PubMed Central

Halpern, Bruno; Oliveira, Eduardo S. L.; Faria, André M.; Halpern, Alfredo; de Melo, Maria Edna; Cercato, Cintia; Mancini, Marcio C.

2010-01-01

Obesity is a chronic disease associated with excess morbidity and mortality. Clinical treatment, however, currently offers disappointing results, with very high rates of weight loss failure or weight regain cycles, and only two drugs (orlistat and sibutramine) approved for long-term use. Drugs combinations can be an option for its treatment but, although widely used in clinical practice, very few data are available in literature for its validation. Our review focuses on the rationale for their use, with advantages and disadvantages; on combinations often used, with or without studies; and on new perspectives of combinations being studied mainly by the pharmaceutical industry. PMID:27713360
“You Are Such a Disappointment!”: Negative Emotions and Parents’ Perceptions of Adult Children’s Lack of Success

PubMed Central

2013-01-01

Objectives. Parents’ perceptions of their adult children’s successes (or lack thereof) may be associated in different ways with discrete negative emotions (e.g., guilt, anger, disappointment, and worry). Furthermore, mothers and fathers may vary in their reactions to children’s success in different domains. Method. Participants included 158 mothers and fathers from the same families (N = 316) and their adult child. Mothers and fathers evaluated their adult children’s successes in (a) career and (b) relationship domains. Mothers and fathers also reported on several negative emotions in the parent–child tie: guilt, anger, disappointment, and worry. Results. For fathers, perceptions of children’s poorer career success were associated with disappointment, anger, and guilt. Mothers’ perceptions of children’s lack of career success were associated with disappointment and worry. Mothers’ perceptions of children’s poorer success in relationships were associated with each of the negative emotions, with the exception of anger. Discussion. Parents experience emotions associated with unmet goals and future concerns in relationships with less successful children. Mothers may respond emotionally to career and relationship success, whereas fathers may respond emotionally primarily to their child’s career success. Findings underscore the importance of considering the context of parents’ negative emotional experiences in ties to adult children. PMID:23733857
Treatment of GORD: Three decades of progress and disappointments

PubMed Central

Galmiche, Jean Paul; Zerbib, Frank

2013-01-01

The treatment of GORD has been revolutionized by the introduction, in the 1980s, of proton-pump inhibitors as the mainstay of medical therapy and by the development of laparoscopic antireflux surgery which has definitively replaced open surgery. However, despite these major advances, many unmet therapeutic needs still persist and justify novel therapeutic approaches. The aim of this historical review is to recall the main discoveries in the treatment of GORD that have occurred during the last three decades and to discuss why some initially promising drugs or techniques have not translated into clinical applications. A careful analysis of these previous disappointing experiences should help to identify high priorities and better research programmes on the management of GORD. PMID:24917952
Leveraging of Open EMR Architecture for Clinical Trial Accrual

PubMed Central

Afrin, Lawrence B.; Oates, James C.; Boyd, Caroline K.; Daniels, Mark S.

2003-01-01

Accrual to clinical trials is a major bottleneck in scientific progress in clinical medicine. Many methods for identifying potential subjects and improving accrual have been pursued; few have succeeded, and none have proven generally reproducible or scalable. We leveraged the open architecture of the core clinical data repository of our electronic medical record system to prototype a solution for this problem in a manner consistent with contemporary regulations and research ethics. We piloted the solution with a local investigator-initiated trial for which candidate identification was expected to be difficult. Key results in the eleven months of experience to date include automated screening of 7,296,708 lab results from 69,288 patients, detection of 1,768 screening tests of interest, identification of 70 potential candidates who met all further automated criteria, and accrual of three candidates to the trial. Hypotheses for this disappointing impact on accrual, and directions for future research, are discussed. PMID:14728125
Implementation of a clinical innovation: the case of advanced clinic access in the Department of Veterans Affairs.

PubMed

Lukas, Carol VanDeusen; Meterko, Mark M; Mohr, David; Seibert, Marjorie Nealon; Parlier, Renee; Levesque, Odette; Petzel, Robert A

2008-01-01

Healthcare organizations seeking to improve clinical practices often have disappointing results because the planned innovations are not successfully implemented. To increase the understanding of implementation, we analyzed the national spread of an ambulatory innovation in the Department of Veterans Affairs. This study provides support for a conceptual model that posits that the extent to which a clinical innovation is implemented will be affected by factors in 3 domains: (1) intentional activities to introduce, spread, and support the innovation; (2) the attitudes and capabilities of clinic staff responsible for implementing the innovation; and (3) the context of the facility in which the innovation is being introduced. Among the strongest predictors of successful implementation, management support for the innovation and clinic team knowledge and skills to make changes successfully were significant across both primary care and specialty clinics.
Parental expression of disappointment: should it be a factor in Hoffman's model of parental discipline?

PubMed

Patrick, Renee B; Gibbs, John C

2007-06-01

The authors addressed whether parental expression of disappointment should be included as a distinct factor in M. L. Hoffman's well-established typology of parenting styles (induction, love withdrawal, power assertion). Hoffman's 3-factor model, along with a more inclusive 4-factor model (induction, love withdrawal, power assertion, and expressions of disappointment), were respectively evaluated in exploratory factor analyses. The analysis utilized extant data comprised of responses by children (N = 73) and their mothers (N = 67) to an adaptation of M. L. Hoffman and H. D. Saltzstein's parental discipline measure. The findings supported Hoffman's original model. Disappointment may be reducible to love withdrawal or induction, although disappointment may be a more appropriate induction for adolescents.
Creating a passion for safety vs. management oversight and inspection

Treesearch

Jim Saveland

1995-01-01

I was disappointed with the OSHA report of the South Canyon Fire. My feelings are not the result of any need to defend my agency (USDA Forest Service). In another time and place, I thought the OSHA report following the death of Bill Martin (a smokejumper who died in a training jump) was right on target. In that instance I was disappointed with my agency's response...
Ethical challenges in preclinical Alzheimer’s disease observational studies and trials: results of the Barcelona summit

PubMed Central

Molinuevo, José L.; Cami, Jordi; Carné, Xavier; Carrillo, Maria C.; Georges, Jean; Isaac, Maria B.; Khachaturian, Zaven; Kim, Scott Y. H.; Morris, John C.; Pasquier, Florence; Ritchie, Craig; Sperling, Reisa; Karlawish, Jason

2016-01-01

Alzheimer’s disease (AD) is among the most significant healthcare burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals’ biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants and disclose or not biomarker status with attention to study type (observational studies versus clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID:26988427

Update on B-cell targeted therapies for systemic lupus erythematosus.

PubMed

Mok, Chi Chiu

2014-06-01

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by flares and remission, leading to accrual of organ damage over time as a result of persistent tissue inflammation and treatment-related complications. Novel therapies aiming at better treatment response and fewer adverse effects are being tested in the pipeline. This review summarizes the B-cell abnormalities observed in patients with SLE, and updates recent data on the efficacy and safety of B-cell targeted therapies in the treatment of SLE. The pitfalls of clinical trial design and future directions of the development of SLE therapeutics are discussed. The variability of clinical response to treatment in SLE reflects the clinical and immunological heterogeneity of the disease. The treatment plan for patients with SLE should be individualized with the aim of eradicating disease activity, preventing flares and minimizing treatment-related complications. Despite the disappointment of recent clinical trials, B-cell remains the promising target of future SLE therapies. Results from ongoing clinical trials on B-cell targeted biological agents are eagerly awaited.
Molecular genetics and genomics progress in urothelial bladder cancer.

PubMed

Netto, George J

2013-11-01

The clinical management of solid tumor patients has recently undergone a paradigm shift as the result of the accelerated advances in cancer genetics and genomics. Molecular diagnostics is now an integral part of routine clinical management in lung, colon, and breast cancer patients. In a disappointing contrast, molecular biomarkers remain largely excluded from current management algorithms of urologic malignancies. The need for new treatment alternatives and validated prognostic molecular biomarkers that can help clinicians identify patients in need of early aggressive management is pressing. Identifying robust predictive biomarkers that can stratify response to newly introduced targeted therapeutics is another crucially needed development. The following is a brief discussion of some promising candidate biomarkers that may soon become a part of clinical management of bladder cancers. © 2013 Published by Elsevier Inc.
Problem-based learning: a review of the educational and psychological theory.

PubMed

Onyon, Clare

2012-02-01

Problem-based learning (PBL) is a teaching method where the use of clinical problems is the starting point for learning, and it is through the process of working through these problems that students acquire the knowledge and skills required to be a doctor. Many advantages of PBL over traditional curricula have been proposed. On reviewing the evidence on the results of PBL curricula for producing better doctors, students tend to perform either a little better or a little worse in examinations. In this article the educational and psychological theories supporting PBL are described. There is a wealth of theory underpinning the use of PBL to teach clinical medicine, despite disappointing results. Future research should concentrate on the reasons behind this uncoupling of theory and outcomes. © Blackwell Publishing Ltd 2012.
Waves of regret: a meg study of emotion and decision-making.

PubMed

Giorgetta, Cinzia; Grecucci, Alessandro; Bonini, Nicolao; Coricelli, Giorgio; Demarchi, Gianpaolo; Braun, Christoph; Sanfey, Alan G

2013-01-01

Recent fMRI studies have investigated brain activity involved in the feeling of regret and disappointment by manipulating the feedback participants saw after making a decision to play certain gambles: full-feedback (regret: participant sees the outcomes from both the chosen and unchosen gamble) vs. partial-feedback (disappointment: participant only sees the outcome from chosen gamble). However, regret and disappointment are also characterized by differential agency attribution: personal agency for regret, external agency for disappointment. In this study, we investigate the neural correlates of these two characterizations of regret and disappointment using magnetoencephalography (MEG). To do this, we experimentally induced each emotion by manipulating feedback (chosen gamble vs. unchosen gamble), agency (human vs. computer choice) and outcomes (win vs. loss) in a fully randomized design. At the behavioral level the emotional experience of regret and disappointment were indeed affected by both feedback and agency manipulations. These emotions also differentially affect subsequent choices, with regret leading to riskier behavior. At the neural level both feedback and agency affected the brain responses associated with regret and disappointment, demonstrating differential localization in the brain for each. Notably, feedback regret showed greater brain activity in the right anterior and posterior regions, with agency regret producing greater activity in the left anterior region. These findings extend the evidence for neural activity in processing both regret and disappointment by highlighting for the first time the respective importance of feedback and agency, as well as outlining the temporal dynamics of these emotions. Copyright © 2012 Elsevier Ltd. All rights reserved.
Novel drugs in clinical development for hepatocellular carcinoma.

PubMed

Waidmann, Oliver; Trojan, Jörg

2015-01-01

Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.
Disappointment with God and Well-Being: The Mediating Influence of Relationship Quality and Dispositional Forgiveness

ERIC Educational Resources Information Center

Strelan, Peter; Acton, Collin; Patrick, Kent

2009-01-01

This study examined the extent to which disappointment with God influenced the psychological and spiritual well-being of 160 churchgoers, and the potential mediating influences of relationship quality (spiritual maturity and relationship commitment) and dispositional forgiveness. Disappointment with God was positively related to depression and…
Addressing disappointment in veterinary practice.

PubMed

O'Connell, Daniel; Bonvicini, Kathleen A

2007-01-01

Disappointing experiences are not uncommon in the increasingly complex setting of veterinary practice. Managing these situations requires that health care teams be sensitive to client disappointments; accept responsibility for engaging with clients to resolve them; and act ethically, sensitively, and flexibly to reach the best resolutions possible while learning from the experience to reduce the potential for recurrence. The reward for their efforts is an enhanced capability to rebuild rapport, trust, credibility, and loyalty after disappointments and adverse outcomes. Success should translate into a more satisfying practice that builds and maintains its client base and minimizes its liability risks.
Transparency in ovarian cancer clinical trial results: ClinicalTrials.gov versus PubMed, Embase and Google scholar.

PubMed

Roberto, Anna; Radrezza, Silvia; Mosconi, Paola

2018-04-10

In recent years the question of the lack of transparency in clinical research has been debated by clinicians, researchers, citizens and their representatives, authors and publishers. This is particularly important for infrequent cancers such as ovarian cancer, where treatment still gives disappointing results in the majority of cases. Our aim was to assess the availability to the public of results in ClinicalTrials.gov, and the frequency of non-publication of results in ClinicalTrials.gov and in PubMed, Embase and Google Scholar. We collected all trials on ovarian cancer identified as "completed status" in the ClinicalTrials.gov registry on 17 January 2017. We checked the availability of the results in ClinicalTrials.gov and systematically identified published manuscripts on results. Out of 2725 trials on ovarian cancer identified, 752 were classified as "completed status". In those closed between 2008 and 2015, excluding phase I, the frequency of results in ClinicalTrials.gov was 35%. Of the 752 completed studies the frequency of published results in PubMed, Embase or Google Scholar ranged from 57.9% to 69.7% in the last years. These findings show a lack of transparency and credibility of research. Citizens or patients' representatives, with the medical community, should continuously support initiatives to improve the publication and dissemination of clinical study results.
Reprint of: B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146(2) 90-103.

PubMed

Furtado, João; Isenberg, David A

2013-09-01

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.
Pessimistic mood in decompensated narcissistic patient.

PubMed

Yang, Ping-Suen; Huang, Tiao-Lai

2004-04-01

We report the negative emotional state as pessimistic mood of a case with narcissistic personality disorder during the period of narcissistic decompensation. In addition, we identified the clinical differences between pessimistic mood and depressive disorder. An 28-year-old unmarried woman experienced herself, her life and the external object as futile and disappointing after repeated failure to satisfy her grandiose fantasies about the search for ideal love. The patient then gave up her formerly gratifying activities, and fell into a prolonged state of negative emotions and passivity dominated by pessimistic mood characterized by an overwhelming sense of futility. The patient did not respond to medical treatment with antidepressants firstly. However after a 2-year course of intensive psychotherapy, the patient was able to restore her zest to find a new boyfriend with a more rational and realistic attitude. Clinically, decompensated narcissistic patients do not exhibit the typical attitude of worthlessness or guilty feelings, and are devoid of certain specific depressive emotions (e.g., sadness, sorrow, etc.). In contrast, decompensated narcissistic patients with pessimistic mood exhibit a dominant sense of futility and other negative emotions presented as outrage and disappointment. The purpose of this case report was to emphasize the importance to recognize clinical features of pessimistic mood for the differential diagnosis and management of the decompensated narcissistic patient.
Behavioral and neural reactions to emotions of others in the distribution of resources.

PubMed

Lelieveld, Gert-Jan; Van Dijk, Eric; Güroğlu, Berna; Van Beest, Ilja; Van Kleef, Gerben A; Rombouts, Serge A R B; Crone, Eveline A

2013-01-01

This study investigated the neural mechanisms involved in the interpersonal effects of emotions--i.e., how people are influenced by other people's emotions. Participants were allocators in a version of the dictator game and made a choice between two offers after receiving written emotional expressions of the recipients. The results showed that participants more often made a self-serving offer when dealing with an angry recipient than when dealing with a happy or disappointed recipient. Compared to disappointment, expressions of anger increased activation in regions associated with self-referential thinking (anterior medial prefrontal cortex, aMPFC) and (emotional) conflict (anterior cingulate cortex). We found increased activation in temporoparietal junction for receiving happy reactions in comparison with receiving angry or disappointed reactions. This study thus emphasizes that distinct emotions have distinct effects on people in terms of behavior and underlying neurological mechanisms.
Spontaneous Regulation of Emotions in Preschool Children Who Stutter: Preliminary Findings

PubMed Central

Johnson, Kia N.; Walden, Tedra A.; Conture, Edward G.; Karrass, Jan

2013-01-01

Purpose Emotional regulation of preschool children who do (CWS) and do not stutter (CWNS) was assessed using a disappointing gift (DG) procedure (Cole, 1986; Saarni, 1984, 1992). Method Participants consisted of 16 3- to 5-year-old CWS and CWNS (11 boys and 5 girls in each talker group). After assessing each child’s knowledge of display rules about socially-appropriate expression of emotions, children participated in a DG procedure and received a desirable gift preceding a free-play task and a disappointing gift preceding a second free-play task. Dependent variables consisted of participants’ positive and negative expressive nonverbal behaviors exhibited during receipt of a desirable gift and disappointing gift, as well as conversational speech disfluencies exhibited following receipt of each gift. Results Findings indicated that CWS and CWNS exhibited no significant differences in amount of positive emotional expressions after receiving the desired gift; however, CWS, when compared to CWNS, exhibited more negative emotional expressions after receiving the undesirable gift. Furthermore, CWS were more disfluent after receiving the desired gift when compared to receiving the disappointing gift. Ancillary findings also indicated that CWS and CWNS had equivalent knowledge of display rules. Conclusion Findings suggest that efforts to concurrently regulate emotional behaviors and (non)stutterings may be problematic for preschool-age CWS. PMID:20643793
Bench-to-bedside review: Inhaled nitric oxide therapy in adults

PubMed Central

Creagh-Brown, Benedict C; Griffiths, Mark JD; Evans, Timothy W

2009-01-01

Nitric oxide (NO) is an endogenous mediator of vascular tone and host defence. Inhaled nitric oxide (iNO) results in preferential pulmonary vasodilatation and lowers pulmonary vascular resistance. The route of administration delivers NO selectively to ventilated lung units so that its effect augments that of hypoxic pulmonary vasoconstriction and improves oxygenation. This 'Bench-to-bedside' review focuses on the mechanisms of action of iNO and its clinical applications, with emphasis on acute lung injury and the acute respiratory distress syndrome. Developments in our understanding of the cellular and molecular actions of NO may help to explain the hitherto disappointing results of randomised controlled trials of iNO. PMID:19519946
Testing the Right Target and the Right Drug at the Right Stage

PubMed Central

Sperling, Reisa A.; Jack, Clifford R.; Aisen, Paul S.

2013-01-01

Alzheimer’s disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness? Alzheimer’s disease (AD) remains one of the most feared consequences of aging, affecting more than one out of every ten individuals over the age of 65. With more than 10,000 baby boomers turning 65 every day in the United States alone, we are truly facing an AD epidemic. Over the past decade, a string of disappointing clinical trial results have raised concerns about our current strategy for development of AD-modifying therapies. Three hypotheses can explain these recent AD trial failures: (i) We are targeting the wrong pathophysiological mechanisms; (ii) The drugs do not engage the intended targets in patients; and (iii) The drugs are hitting the right targets, but are doing so at the wrong stage of the disease. Here, we address the third supposition and suggest that specific amyloid-based therapies be directed at much earlier stages of ADperhaps even prior to the emergence of clinical symptoms. Furthermore, we argue that the field has sufficient tools to begin “secondary prevention” trials in asymptomatic individuals whoare at high risk for progression to cognitive impairment and AD dementia. PMID:22133718
Progress with oocyte cryopreservation.

PubMed

Porcu, Eleonora; Venturoli, Stefano

2006-06-01

This article reviews human oocyte cryopreservation, one of the most stimulating challenges of assisted reproduction technology. Since the first steps in assisted reproduction technology, researchers have pursued this goal, to greatly improve the management of infertility treatments. This present review depicts the present state of research and clinical applications of this methodology. Recent literature focuses on the possible mechanisms of oocyte damage caused by temperature and cryoprotectant injury and forecasts possible technological solutions. Several papers illustrate encouraging results in the increasing clinical application of this procedure. Findings give support to several indications of human female gamete cryostorage. Oocyte cryopreservation might replace embryo freezing. Egg freezing offers an alternative to women at risk of losing their reproductive function, caused by antineoplastic treatments, endometriosis, ovarian surgery or genetic premature ovarian failure. In addition, oocyte storage may contribute to an increase in in-vitro fertilization flexibility. Despite the early disappointing results, recent technical modifications have improved the clinical efficiency greatly, with the birth of several healthy children.
[Mesenchymal stem cell therapy, a new hope for eye disease].

PubMed

Roubeix, C; Denoyer, A; Brignole-Baudouin, F; Baudouin, C

2015-10-01

Mesenchymal stem cells (MSC) are adult stem cells, first identified in skeletal tissues and then found in the entire body. MSC are able to not only differentiate into specialized cells within skeletal tissue - chondrocytes, osteocytes, adipocytes and fibroblasts - but also secrete a large range of soluble mediators defining their secretome and allowing their interaction with a number of cell protagonists. Thus, in a general sense, MSC are involved in tissue homeostasis through their secretome and are specifically responsible for cell turn-over in skeletal tissues. For a decade and a half, safety and efficiency of MSC has led to the development of many clinical trials in various fields. However, results were often disappointing, probably because of difficulties in methods and evaluation. At a time when the first clinical trials using MSC are emerging in ophthalmology, the goal of this literature review is to gather and put into perspective preclinical and clinical results in order to better predict the future of this innovative therapeutic pathway. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Feelings of regret and disappointment in adults with high-functioning autism.

PubMed

Zalla, Tiziana; Sirigu, Angela; Robic, Suzanne; Chaste, Pauline; Leboyer, Marion; Coricelli, Giorgio

2014-09-01

Impairments in emotional processing in Autism Spectrum Disorders (ASDs) can be characterised by failure to generate and recognize self-reflective, cognitive-based emotions, such as pride, embarrassment and shame. Among this type of emotions, regret and disappointment, as well as their positive counterparts, result from a counterfactual comparison, that is the comparison between an actual value ("what is") and a fictive value ("what might have been"). However, while disappointment is experienced when the obtained outcome is worse than the expected outcome that might have occurred from the same choice, regret occurs when one experiences an outcome that is worse than the outcome of foregone choices. By manipulating a simple gambling task, we examined subjective reports on the intensity of negative and positive emotions in a group of adults with High-Functioning Autism or Asperger syndrome (HFA/AS), and a control group matched for age, gender and educational level. Participants were asked to choose between two lotteries with different levels of risk under two conditions of outcome feedback: (i) Partial, in which only the outcome of the chosen lottery was visible, (ii) Complete, in which the outcomes of the two lotteries were simultaneously visible. By comparing partial and complete conditions, we aimed to investigate the differential effect between disappointment and regret, as well as between their positive counterparts. Relative to the control participants (CP), the group with HFA/AS reported reduced regret and no difference between regret and disappointment, along with a preserved ability to use counterfactual thinking and similar choice behaviour. Difficulties to distinguish the feeling of regret in participants with HFA/AS can be explained by diminished emotional awareness, likely associated with an abnormal fronto-limbic connectivity. Copyright © 2014 Elsevier Ltd. All rights reserved.
The Role of the Insulin/IGF System in Cancer: Lessons Learned from Clinical Trials and the Energy Balance-Cancer Link

PubMed Central

Bowers, Laura W.; Rossi, Emily L.; O’Flanagan, Ciara H.; deGraffenried, Linda A.; Hursting, Stephen D.

2015-01-01

Numerous epidemiological and pre-clinical studies have demonstrated that the insulin/insulin-like growth factor (IGF) system plays a key role in the development and progression of several types of cancer. Insulin/IGF signaling, in cooperation with chronic low-grade inflammation, is also an important contributor to the cancer-promoting effects of obesity. However, clinical trials for drugs targeting different components of this system have produced largely disappointing results, possibly due to the lack of predictive biomarker use and problems with the design of combination therapy regimens. With careful attention to the identification of likely patient responders and optimal drug combinations, the outcome of future trials may be improved. Given that insulin/IGF signaling is known to contribute to obesity-associated cancer, further investigation regarding the efficacy of drugs targeting this system and its downstream effectors in the obese patient population is warranted. PMID:26029167
Key issues in the management of patients with systemic lupus erythematosus: latest developments and clinical implications

PubMed Central

Jordan, Natasha; D’Cruz, David

2015-01-01

Systemic lupus erythematous (SLE) is a chronic multisystem disease with significant associated morbidity and mortality. A deeper understanding of the pathogenesis of SLE has led to the development of biologic agents, primarily targeting B cells and others inhibiting costimulatory molecules, type I interferons and cytokines such as interleukin-6. Several of these agents have been studied in clinical trials; some have shown promise while others have yielded disappointing results. Economic and regulatory issues continue to hamper the availability of such therapies for SLE patients. With increasing recognition that recurrent flares of disease activity lead to long-term damage accrual, one of the most important recent developments in patient management has been the concept of treat-to-target in SLE while minimizing patient exposure to excessive corticosteroid and other immunosuppressive therapy. This article reviews these key issues in SLE management, outlining recent developments and clinical implications for patients. PMID:26622325
Pharmacogenetics and personalised medicine: maintain a critical approach.

PubMed

2013-06-01

The purpose of pharmacogenetics is to offer"personalised" treatment, in which a drug is only prescribed to patients in whom it is very likely to be effective, or to withhold a drug from patients at increased risk of adverse effects. Pharmacogenetics requires the use of genetic tests which, as with any other diagnostic test, must be evaluated for their discriminatory power (sensitivity, specificity, etc.). These evaluations are sometimes biased. Pharmacogenetics has been heralded as a means of tailoring cancer therapy. However large clinical trials with demanding clinical endpoints are often disappointing, despite initially encouraging results. Pharmacogenetic information is included in many summaries of product characteristics for non-cancer drugs, mainly in order to reduce the frequency of certain serious adverse effects. In summary, pharmacogenetics theoretically represents a step forward but must be evaluated in rigorous clinical trials, as is the case with all other "therapeutic tools".

Not so Fast: Co-Requirements for Sonic Hedgehog Induced Brain Tumorigenesis.

PubMed

Ward, Stacey A; Rubin, Joshua B

2015-08-06

The Sonic hedgehog (Shh) pathway plays an integral role in cellular proliferation during normal brain development and also drives growth in a variety of cancers including brain cancer. Clinical trials of Shh pathway inhibitors for brain tumors have yielded disappointing results, indicating a more nuanced role for Shh signaling. We postulate that Shh signaling does not work alone but requires co-activation of other signaling pathways for tumorigenesis and stem cell maintenance. This review will focus on the interplay between the Shh pathway and these pathways to promote tumor growth in brain tumors, presenting opportunities for the study of combinatorial therapies.
Exogenous Ochronosis

PubMed Central

Bhattar, Prachi A; Zawar, Vijay P; Godse, Kiran V; Patil, Sharmila P; Nadkarni, Nitin J; Gautam, Manjyot M

2015-01-01

Exogenous ochronosis (EO) is a cutaneous disorder characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone but may also occur due to topical contact with phenol or resorcinol in dark-skinned individuals. It can also occur following the use of systemic antimalarials such as quinine. EO is clinically and histologically similar to its endogenous counterpart viz., alkaptonuria, which, however, exhibits systemic effects and is an inherited disorder. Dermoscopy and in vivo skin reflectance confocal microscopy are noninvasive in vivo diagnostic tools. It is very difficult to treat EO, a cosmetically disfiguring and troubling disorder with disappointing treatment options. PMID:26677264
Granulomatous slack skin. Histopathology diagnosis preceding clinical manifestations by 12 years.

PubMed

Goldsztajn, Karen O; Moritz Trope, Beatriz; Ribeiro Lenzi, Maria Elisa; Cuzzi, Tullia; Ramos-E-Silva, Marcia

2012-12-31

Granulomatous slack skin is a very rare subtype of T-cell cutaneous lymphoma, characterized by the slow development of cutaneous sagging, especially on flexural areas. Its behavior is indolent and the treatment, in the majority of cases, disappointing. We report a 54-year-old black patient with granulomatous slack skin, who at the beginning of the investigation showed intense xeroderma and generalized lymph node enlargement. The diagnosis was established based on histopathologic findings long before the disease's characteristic clinical presentation appeared. During the twelve years of follow-up, the clinical manifestation evolved to marked skin looseness, most predominant in flexural regions, illustrating the clinical hallmark of granulomatous slack skin, long after first histological abnormalities were observed.
Expectations for Weight Loss and Willingness to Accept Risk Among Patients Seeking Weight Loss Surgery

PubMed Central

Wee, Christina C.; Hamel, Mary Beth; Apovian, Caroline M.; Blackburn, George L.; Bolcic-Jankovic, Dragana; Colten, Mary Ellen; Hess, Donald T.; Huskey, Karen W.; Marcantonio, Edward R.; Schneider, Benjamin E.; Jones, Daniel B.

2015-01-01

Importance Weight loss surgery (WLS) has been shown to produce long-term weight loss but is not risk free or universally effective. The weight loss expectations and willingness to undergo perioperative risk among patients seeking WLS remain unknown. Objectives To examine the expectations and motivations of WLS patients and the mortality risks they are willing to undertake and to explore the demographic characteristics, clinical factors, and patient perceptions associated with high weight loss expectations and willingness to assume high surgical risk. Design We interviewed patients seeking WLS and conducted multivariable analyses to examine the characteristics associated with high weight loss expectations and the acceptance of mortality risks of 10% or higher. Setting Two WLS centers in Boston. Participants Six hundred fifty-four patients. Main Outcome Measures Disappointment with a sustained weight loss of 20% and willingness to accept a mortality risk of 10% or higher with WLS. Results On average, patients expected to lose as much as 38% of their weight after WLS and expressed disappointment if they did not lose at least 26%. Most patients (84.8%) accepted some risk of dying to undergo WLS, but only 57.5% were willing to undergo a hypothetical treatment that produced a 20% weight loss. The mean acceptable mortality risk to undergo WLS was 6.7%, but the median risk was only 0.1%; 19.5% of all patients were willing to accept a risk of at least 10%. Women were more likely than men to be disappointed with a 20% weight loss but were less likely to accept high mortality risk. After initial adjustment, white patients appeared more likely than African American patients to have high weight loss expectations and to be willing to accept high risk. Patients with lower quality-of-life scores and those who perceived needing to lose more than 10% and 20% of weight to achieve “any” health benefits were more likely to have unrealistic weight loss expectations. Low quality-of-life scores were also associated with willingness to accept high risk. Conclusions and Relevance Most patients seeking WLS have high weight loss expectations and believe they need to lose substantial weight to derive any health benefits. Educational efforts may be necessary to align expectations with clinical reality. PMID:23553327
"You are such a disappointment!": negative emotions and parents' perceptions of adult children's lack of success.

PubMed

Cichy, Kelly E; Lefkowitz, Eva S; Davis, Eden M; Fingerman, Karen L

2013-11-01

Parents' perceptions of their adult children's successes (or lack thereof) may be associated in different ways with discrete negative emotions (e.g., guilt, anger, disappointment, and worry). Furthermore, mothers and fathers may vary in their reactions to children's success in different domains. Participants included 158 mothers and fathers from the same families (N = 316) and their adult child. Mothers and fathers evaluated their adult children's successes in (a) career and (b) relationship domains. Mothers and fathers also reported on several negative emotions in the parent-child tie: guilt, anger, disappointment, and worry. For fathers, perceptions of children's poorer career success were associated with disappointment, anger, and guilt. Mothers' perceptions of children's lack of career success were associated with disappointment and worry. Mothers' perceptions of children's poorer success in relationships were associated with each of the negative emotions, with the exception of anger. Parents experience emotions associated with unmet goals and future concerns in relationships with less successful children. Mothers may respond emotionally to career and relationship success, whereas fathers may respond emotionally primarily to their child's career success. Findings underscore the importance of considering the context of parents' negative emotional experiences in ties to adult children.
The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey

PubMed Central

Turner, Martin R; Swash, Michael

2015-01-01

Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS. PMID:25644224
75 FR 16129 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-31

... use the Internet as a virtual collaborative met with disappointing results. Another barrier to... while attending to their financial realities. The result was Implementing Integrating Chronic Care and...
Multi-Family Group Intervention for OEF/OIF Traumatic Brain Injury Survivors and their Families

DTIC Science & Technology

2011-10-01

protocol. For example, due to a high degree of marital conflict observed in two couples in the initial Bronx group, the second group incorporated...veterans’ family members. Insufficient information can exacerbate marital or family conflict and lead to psychological distress and social isolation...disappointment, frustration, family conflict , and child distress (Collins & Kennedy, KRISTY STRAITS-TRÖSTER received her PhD in clinical psychology from the
My Pride and Joy? Predicting Favoritism and Disfavoritism in Mother-Adult Child Relations.

PubMed

Suitor, J Jill; Gilligan, Megan; Peng, Siyun; Con, Gulcin; Rurka, Marissa; Pillemer, Karl

2016-08-01

In this article, we compare predictors of mothers' differentiation among their adult children regarding emotional closeness, pride, conflict, and disappointment. We distinguish between predictors of relational (closeness, conflict) and evaluative (pride, disappointment) dimensions of favoritism and disfavoritism. Multilevel modeling using data collected from 381 older mothers regarding their relationships with 1,421 adult children indicated that adult children's similarity of values played the most prominent role in predicting mothers' favoritism and disfavoritism, followed by children's gender. Children's deviant behaviors in adulthood predicted both pride and disappointment but neither relational dimension. Contrary to expectations, the quantitative analysis indicated that children's normative adult achievements were poor predictors of both relational and evaluative dimensions of mothers' differentiation. Qualitative data shed additional light on mothers' evaluations by revealing that disappointment was shaped by children's achievements relative to their mothers' values and expectations, rather than by the achievement of specific societal, educational, career, and marital milestones.
The road ahead: working towards effective clinical translation of myocardial gene therapies

PubMed Central

Katz, Michael G; Fargnoli, Anthony S; Williams, Richard D; Bridges, Charles R

2014-01-01

During the last two decades the fields of molecular and cellular cardiology, and more recently molecular cardiac surgery, have developed rapidly. The concept of delivering cDNA encoding a therapeutic gene to cardiomyocytes using a vector system with substantial cardiac tropism, allowing for long-term expression of a therapeutic protein, has moved from hypothesis to bench to clinical application. However, the clinical results to date are still disappointing. The ideal gene transfer method should be explored in clinically relevant animal models of heart disease to evaluate the relative roles of specific molecular pathways in disease pathogenesis, helping to validate the potential targets for therapeutic intervention. Successful clinical cardiovascular gene therapy also requires the use of nonimmunogenic cardiotropic vectors capable of expressing the requisite amount of therapeutic protein in vivo and in situ. Depending on the desired application either regional or global myocardial gene delivery is required. Cardiac-specific delivery techniques incorporating mapping technologies for regional delivery and highly efficient methodologies for global delivery should improve the precision and specificity of gene transfer to the areas of interest and minimize collateral organ gene expression. PMID:24341816
What RA patients expect of their treatment--discussion over the result of our survey.

PubMed

Funahashi, Keiko; Matsubara, Tsukasa

2012-11-01

We conducted a survey among Japanese rheumatoid arthritis (RA) patients to better understand what they expect from treatment and whether there is a difference between expectations of biologics-treated and disease-modifying antirheumatic drugs (DMARDs)-treated patients. An anonymous survey was conducted with 165 outpatients from our clinic (with informed written consent). On the survey, they wrote their age, gender, medical history, and commented on: (1) expectations for treatment, (2) disappointment with treatment, (3) experience of, and thoughts about switching treatments, (4) information wanted before starting a new treatment, (5) expectations before administration and noticeable differences after treatment, (6) level of satisfaction with current treatment, and (7) expectations of possible treatments. Patients who had never been treated with DMARDs were excluded from the survey. For "treatment goals before administration," 86 % responded with "assured efficacy," while 73 % responded "suppress joint destruction" or "recover from joint destruction." Also, more patients hoped for "long-lasting efficacy" (67 %) over "fast acting" (41 %), which suggests significance of the long-term improvement of QOL. Related to "disappointment with treatment," patients also felt anxiety over switching treatment for possibilities of not responding enough, or side effects. RA patients have high expectations for medication in terms of assured improvement of conditions and long-lasting efficacy of drugs, while the biggest concern was if they would have side effects or not, and if so, what type. The results suggest patients hope to have worries over switching medications dispelled. The results also verified those who have used biologics before have higher treatment goals than those who have not.
[Calcifications after intra-disk injection of triamcinolone hexacetonide in lumbar disk hernia. Evaluation of therapeutical results in 3 years].

PubMed

Debiais, F; Bontoux, D; Alcalay, M; Vandermarcq, P; Azais, O; Denis, A; Azais, I; Gasquet, C

1991-10-01

The development of disk or epidural calcifications is a frequent possibility following intra-disk injection of triamcinolone hexacetonide. It was found 10 times in 26 follow-up CT scans obtained 2 to 3 years after the injection. These calcifications are often clinically silent, but they sometimes accompany a recurrence of the initial painful symptomatology. Furthermore, evaluation at 3 years of therapeutic results in a previously published series of patients who had received an intra-disk injection of triamcinolone hexacetonide showed a marked decrease in favourable results (30% vs 67% at 6 months). These two arguments: disappointing long term results and possibility of disk calcifications, are felt by the authors to justify abandoning the technique of triamcinolone hexacetonide by intra-disk injection in the treatment of lumbar disk prolapse.
Update on the use of alitretinoin in treating chronic hand eczema.

PubMed

Ghasri, Pedram; Scheinfeld, Noah

2010-04-19

Chronic hand eczema is a debilitating dermatological condition with significant economic, social, and functional impacts. To date, conventional treatments such as topical corticosteroids, phototherapy, and systemic immunosuppressants have yielded disappointing results, owing to either a lack of efficacy or significant adverse events. Oral alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid with immunomodulatory and anti-inflammatory activity that has emerged as a novel treatment for chronic hand eczema. Several large-scale clinical studies have demonstrated oral alitretinoin's high efficacy rate of 28% to 89%, its safe tolerability profile, and its positive impact on quality of life, validating it as a therapeutic option for patients with severe chronic hand eczema refractory to standard treatment.
Use of regenerative tissue for urinary diversion.

PubMed

Sopko, Nikolai A; Kates, Max; Bivalacqua, Trinity J

2015-11-01

There is a large interest in developing tissue engineered urinary diversions (TEUDs) in order to reduce the significant morbidity that results from utilization of the alimentary tract in the urinary system. Preclinical trials have been favorable but durable clinical results have not been realized. The present article will review the pertinent concepts for the clinical development of a successful TEUD. Studies continue to identify novel scaffold materials and cell populations that are combined to generate TEUDs. Scaffold composition range from synthetic material to decelluarized bladder tissue. Cell types vary from fully differentiated adult populations such as smooth muscle cells isolated from the bladder to stem cell populations including mesenchymal stem cells and induced pluripotent stem cells. Each scaffold and cell type has its advantages and disadvantages with no clear superior component having been identified. Recent clinical trials have been disappointing, supporting the need for additional investigation. Successful application of TEUDs requires a complex interplay of scaffold, cells, and host environment. Studies continue to investigate candidate scaffold materials, cell populations, and combinations thereof to determine which will best recapitulate the complex structure of the human genitourinary tract.
75 FR 5081 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-01

... virtual collaborative met with disappointing results. Another barrier to adoption of the CCM in settings... realities. The result was Implementing Integrating Chronic Care and Business Strategies in the Safety Net. A...
Transformed by Disappointment

ERIC Educational Resources Information Center

Hall, Karen E.

2011-01-01

American author Napoleon Hill stated that "with every disappointment, heartbreak, or failure, there exists an equal (usually greater) positive benefit." In this article, the author shares how weathering her own personal storms has helped her to guide her students to the learning opportunities inherent in their challenges. Her experience with the…
Repeat migration and disappointment.

PubMed

Grant, E K; Vanderkamp, J

1986-01-01

This article investigates the determinants of repeat migration among the 44 regions of Canada, using information from a large micro-database which spans the period 1968 to 1971. The explanation of repeat migration probabilities is a difficult task, and this attempt is only partly successful. May of the explanatory variables are not significant, and the overall explanatory power of the equations is not high. In the area of personal characteristics, the variables related to age, sex, and marital status are generally significant and with expected signs. The distance variable has a strongly positive effect on onward move probabilities. Variables related to prior migration experience have an important impact that differs between return and onward probabilities. In particular, the occurrence of prior moves has a striking effect on the probability of onward migration. The variable representing disappointment, or relative success of the initial move, plays a significant role in explaining repeat migration probabilities. The disappointment variable represents the ratio of actural versus expected wage income in the year after the initial move, and its effect on both repeat migration probabilities is always negative and almost always highly significant. The repeat probabilities diminish after a year's stay in the destination region, but disappointment in the most recent year still has a bearing on the delayed repeat probabilities. While the quantitative impact of the disappointment variable is not large, it is difficult to draw comparisons since similar estimates are not available elsewhere.
An Integral Study of Galactic Black Hole States

NASA Technical Reports Server (NTRS)

2005-01-01

XTE 51550-564 was clearly detected with INTEGRAL out to 600 keV with the SPI, and is one of only two sources detected with IBISPICSIT. Software difficulties in analyzing the data prevented us from progressing with the analysis past the most elementary stages (see last year's report). The support from the INTEGRAL help desk has been very disappointing. People affiliated with INTEGRAL published a paper on the results of our data before we could master the reduction and analysis software. We are not the only group that got stuck with the analysis without adequate support from the INTEGRAL help desk. This was a rather disappointing experience as we lost many months of valuable time and efforts.
Educational Orientation and Upward Influence: An Examination of Students' Conversations about Disappointing Grades

ERIC Educational Resources Information Center

Wright, Courtney N.

2012-01-01

The influence of student attitudes toward learning and grades on their communication with instructors about grades has received limited attention despite its potential implications for learning, performance outcomes, and student-teacher interactions. Participants (N = 194) who discussed a disappointing grade with an instructor completed measures…
Application of topical mitomycin C to the base of shave-removed keloid scars to prevent their recurrence.

PubMed

Bailey, J N R; Waite, A E; Clayton, W J; Rustin, M H A

2007-04-01

Keloid scars are formed by over-activity of fibroblasts producing collagen and they cause significant morbidity both from their appearance and from their symptoms. Existing treatments are often unsatisfactory. Topical mitomycin C is known to inhibit fibroblast proliferation. To determine whether application of mitomycin C to the base of shave-removed keloids would prevent their recurrence. Ten patients had all or part of their keloid shave-removed. After haemostasis topical mitomycin C 1 mg mL(-1) was applied for 3 min. This application was repeated after 3 weeks. The keloids were photographed before treatment and the patients were reviewed every 2 months for a total of 6 months when a final photograph of the keloid site was taken. The patients and the Clinical Trials Unit staff scored the outcome on a linear analogue scale of 0-10, where 0 = disappointed and 10 = delighted. The pretreatment and 6-month post-treatment photographs were also assessed by two dermatologists who were not involved in the clinical trial. Four of the 10 patients were delighted with the outcome of treatment and only one was disappointed. On average there was an 80% satisfied outcome. This new treatment of keloids has been shown to be effective in the majority of patients but further studies are required to confirm this benefit.

The continuing challenge of parastomal hernia: failure of a novel polypropylene mesh repair.

PubMed Central

Morris-Stiff, G.; Hughes, L. E.

1998-01-01

In an attempt to reduce the high recurrence rate after repair of parastomal hernia, a technique was devised in which non-absorbable mesh was used to provide a permanent closure of the gap between the emerging bowel and abdominal wall. Seven patients were treated during the period 1990-1992. Five-year follow-up has given disappointing results, with recurrent hernia in 29% of cases and serious complications, including obstruction and dense adhesions to the intra-abdominal mesh, in 57% and a mesh-related abscess in 15% of cases. This study highlights a dual problem--failure of a carefully sutured mesh to maintain an occlusive position, and complications of the mesh itself. The poor results obtained with this technique together with the disappointing results with other methods described in the literature confirms that parastomal hernia presents a continuing challenge. Images Figure 1 Figure 2 PMID:9682640
Update on the use of alitretinoin in treating chronic hand eczema

PubMed Central

Ghasri, Pedram; Scheinfeld, Noah

2010-01-01

Chronic hand eczema is a debilitating dermatological condition with significant economic, social, and functional impacts. To date, conventional treatments such as topical corticosteroids, phototherapy, and systemic immunosuppressants have yielded disappointing results, owing to either a lack of efficacy or significant adverse events. Oral alitretinoin (9-cis-retinoic acid) is a unique panagonist retinoid with immunomodulatory and anti-inflammatory activity that has emerged as a novel treatment for chronic hand eczema. Several large-scale clinical studies have demonstrated oral alitretinoin’s high efficacy rate of 28% to 89%, its safe tolerability profile, and its positive impact on quality of life, validating it as a therapeutic option for patients with severe chronic hand eczema refractory to standard treatment. PMID:21437060
Metabolic immune restraints: implications for anticancer vaccines.

PubMed

Mocellin, Simone

2010-01-01

Metabolic immune restraints belong to a highly complex network of molecular mechanisms underlying the failure of naturally occurring and therapeutically induced immune responses against cancer. In the light of the disappointing results yielded so far with anticancer vaccines in the clinical setting, the dissection of the cascade of molecular events leading to tumor immune escape appears the most promising way to develop more effective immunotherapeutic strategies. Here we review the significant advances recently made in the understanding of the tumor-specific metabolic features that contribute to keep malignant cells from being recognized and destroyed by immune effectors. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits and thus to enhance the effectiveness of anticancer vaccines.
[Tumour anorexia--tumour cachexia in case of gastrointestinal tumours: standards and visions].

PubMed

Ockenga, J; Pirlich, M; Gastell, S; Lochs, H

2002-11-01

The development of progressive malnutrition or cachexia is frequent in patients with gastrointestinal cancer - especially in patients with a carcinoma of the pancreas. The cachexia syndrome which is characterised by loss of body weight, negative nitrogen balance and fatigue significantly affects patients' quality of life, morbidity and survival. Because the currently established therapeutical strategies are often disappointing many physicians tended to develop a therapeutical nihilism. Cancer anorexia and cachexia are two distinct syndromes which may have synergistic effects in a patient. This review highlights the growing understanding of the multidimensional pathophysiological background. An algorithm of the current treatment strategies is given. In addition, we discuss new anabolic and anticatabolic agents (e.g. eicosapentanoic acid) and the results from first clinical trials.
Patient preferences and performance bias in a weight loss trial with a usual care arm☆☆☆

PubMed Central

McCambridge, Jim; Sorhaindo, Annik; Quirk, Alan; Nanchahal, Kiran

2014-01-01

Objectives This qualitative study examines performance bias, i.e. unintended differences between groups, in the context of a weight loss trial in which a novel patient counseling program was compared to usual care in general practice. Methods 14/381 consecutive interviewees (6 intervention group, 8 control group) within the CAMWEL (Camden Weight Loss) effectiveness trial process study were asked about their engagement with various features of the research study and a thematic content analysis undertaken. Results Decisions to participate were interwoven with decisions to change behavior, to the extent that for many participants the two were synonymous. The intervention group were satisfied with their allocation. The control group spoke of their disappointment at having been offered usual care when they had taken part in the trial to access new forms of help. Reactions to disappointment involved both movements toward and away from behavior change. Conclusion There is a prima facie case that reactions to disappointment may introduce bias, as they lead the randomized groups to differ in ways other than the intended experimental contrast. Practice implications In-depth qualitative studies nested within trials are needed to understand better the processes through which bias may be introduced. PMID:24492159
Experiences of being a control group: lessons from a UK-based randomized controlled trial of group singing as a health promotion initiative for older people.

PubMed

Skingley, Ann; Bungay, Hilary; Clift, Stephen; Warden, June

2014-12-01

Existing randomized controlled trials within the health field suggest that the concept of randomization is not always well understood and that feelings of disappointment may occur when participants are not placed in their preferred arm. This may affect a study's rigour and ethical integrity if not addressed. We aimed to test whether these issues apply to a healthy volunteer sample within a health promotion trial of singing for older people. Written comments from control group participants at two points during the trial were analysed, together with individual semi-structured interviews with a small sample (n = 11) of this group. We found that motivation to participate in the trial was largely due to the appeal of singing and disappointment resulted from allocation to the control group. Understanding of randomization was generally good and feelings of disappointment lessened over time and with a post-research opportunity to sing. Findings suggest that measures should be put in place to minimize the potential negative impacts of randomized controlled trials in health promotion research. © The Author (2013). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
"He Didn't Want Me to Feel Sad": Children's Reactions to Disappointment and Apology

ERIC Educational Resources Information Center

Smith, Craig E.; Harris, Paul L.

2012-01-01

Experimental studies of children's responses to apologies often present participants with hypothetical scenarios. This article reports on an experimental study of children's reactions to experiencing an actual disappointment and subsequent apology. Participants (ages four to seven) were told that another child was supposed to share some attractive…
The Influence of Counterfactual Thinking and Regret on Ethical Decision Making

ERIC Educational Resources Information Center

Celuch, Kevin; Saxby, Carl; Oeding, Jill

2015-01-01

The authors explore the influence of counterfactual thoughts in triggering the emotions of regret and disappointment in ethical decision making. Counterfactual thinking involves examining possible outcomes to events and is often explored in what-if scenarios. Findings support that subjects were able to transfer regret (but not disappointment)…
A Comparison of Expectations of Physicians and Patients with Chronic Pain for Pain Clinic Visits.

PubMed

Calpin, Pádraig; Imran, Ather; Harmon, Dominic

2017-03-01

The patient-physician encounter forms the cornerstone of every health service. However, optimal medical outcomes are often confounded by inadequate patient-physician communication. Chronic pain is estimated to affect over 25% of the population. Its effects are multifaceted with patients at increased risk of experiencing emotional and functional disturbances. Therefore, it is crucial to address all components of the patient's pain experience, including beliefs and expectations. It is our understanding that no other study to date has evaluated the expectations of physicians and compared them to those of patients for pain clinic visits. We sought to describe and compare expectations of chronic pain patients and their physicians during a clinic consultation. We performed a retrospective review on patients attending the pain clinic for the first time who were enrolled and completed a questionnaire asking their expectations for their clinic visit as well as outcomes that would satisfy and disappoint them. Pain physicians were also included. We compared physicians' to patients' responses and evaluated relationships between patient responses and age, gender, pain location, Pain Self-Efficacy, Pain Catastrophizing Scale, and the Hospital Anxiety and Depression Scale. One hundred chronic pain patients and 10 pain physicians were surveyed. Patients' clinical expectations for visits focused primarily on some pain relief (34%), education on the cause of pain (24%), and a definitive diagnosis (18%). Physician's expectations included formulation and communication of a management plan (70%), patient assessment for cause of pain (50%), and the education of patients on the cause of pain (40%) as important aims. Pain relief would satisfy the majority of patients (74%) and physicians (70%). No improvement would cause greatest dissatisfaction for patients (52%), but causing more harm would be disappointing to physicians (50%). Gender, age, pain location, and sleep quality all significantly influenced patients' expectations and affective pain comorbidities. We found some agreement and some discordance of clinical expectations between pain patients and physicians. Patient factors may also impact on expectations and comorbidities. Findings from this study will help doctors consider patients' expectations in planning pain clinic visits, improve patient-doctor communication and pain management, and may lead to further hypothesis-driven studies. © 2016 World Institute of Pain.
Twenty Years of Social Studies Textbook Content Analysis: Still "Decidedly Disappointing"?

ERIC Educational Resources Information Center

Chu, Yiting

2017-01-01

In an article published in 1993, Rahima Wade reviewed the quality of social studies textbook content analyses published in three major social studies journals between 1982 and 1992. She concluded that the quality of this research was disappointing. Borrowing and refining Wade's methods, this article presents the findings of a review of all 29…
Parental Expression of Disappointment: Should It Be a Factor in Hoffman's Model of Parental Discipline?

ERIC Educational Resources Information Center

Patrick, Renee B.; Gibbs, John C.

2007-01-01

The authors addressed whether parental expression of disappointment should be included as a distinct factor in M. L. Hoffman's (2000) well-established typology of parenting styles (induction, love withdrawal, power assertion). Hoffman's 3-factor model, along with a more inclusive 4-factor model (induction, love withdrawal, power assertion, and…
"Fisher v. Texas": Strictly Disappointing

ERIC Educational Resources Information Center

Nieli, Russell K.

2013-01-01

Russell K. Nieli writes in this opinion paper that as far as the ability of state colleges and universities to use race as a criteria for admission goes, "Fisher v. Texas" was a big disappointment, and failed in the most basic way. Nieli states that although some affirmative action opponents have tried to put a more positive spin on the…
Preschoolers' Effortful Control and Negative Emotionality, Immediate Reactions to Disappointment, and Quality of Social Functioning

ERIC Educational Resources Information Center

Liew, Jeffrey; Eisenberg, Nancy; Reiser, Mark

2004-01-01

Relations among effortful control/low negative emotionality, immediate reactions in a situation that usually calls for the masking of disappointment (i.e., the use of display rules), and social competence/adjustment were investigated for 78 preschool children (mean age=4.87 years). Parents, teachers, and peers rated children on negative…
FGFR-targeted therapeutics for the treatment of breast cancer.

PubMed

De Luca, Antonella; Frezzetti, Daniela; Gallo, Marianna; Normanno, Nicola

2017-03-01

Breast cancer is a complex disease and several molecular drivers regulate its progression. Fibroblast growth factor receptor (FGFR) signaling is frequently deregulated in many cancers, including breast cancer. Due the involvement of the FGFR/FGF axis in the pathogenesis and progression of tumors, FGFR-targeted agents might represent a potential therapeutic option for breast cancer patients. Areas covered: This review offers an overview of targeted agents against FGFRs and their clinical development in breast cancer. The most relevant literature and the latest studies in the Clinicaltrial.com database have been discussed. Expert opinion: FGFR inhibition has been recently considered as a promising therapeutic option for different tumor types. However, preliminary results of clinical trials of FGFR inhibitors in breast cancer have been quite disappointing. In order to increase the clinical benefit of FGFR therapies in breast cancer, future studies should focus on: understanding the role of the various FGFR aberrations in cancer progression; identifying potential biomarkers to select patients that could benefit of FGFR inhibitors and developing therapeutic strategies that improve the efficacy of these agents and minimize toxicities.
Controversies and Evolving New Mechanisms in Subarachnoid Hemorrhage

PubMed Central

Chen, Sheng; Feng, Hua; Sherchan, Prativa; Klebe, Damon; Zhao, Gang; Sun, Xiaochuan; Zhang, Jianmin; Tang, Jiping; Zhang, John H.

2013-01-01

Despite decades of study, subarachnoid hemorrhage (SAH) continues to be a serious and significant health problem in the United States and worldwide. The mechanisms contributing to brain injury after SAH remain unclear. Traditionally, most in vivo research has heavily emphasized the basic mechanisms of SAH over the pathophysiological or morphological changes of delayed cerebral vasospasm after SAH. Unfortunately, the results of clinical trials based on this premise have mostly been disappointing, implicating some other pathophysiological factors, independent of vasospasm, as contributors to poor clinical outcomes. Delayed cerebral vasospasm is no longer the only culprit. In this review, we summarize recent data from both experimental and clinical studies of SAH and discuss the vast array of physiological dysfunctions following SAH that ultimately lead to cell death. Based on the progress in neurobiological understanding of SAH, the terms “early brain injury” and “delayed brain injury” are used according to the temporal progression of SAH-induced brain injury. Additionally, a new concept of the vasculo-neuronal-glia triad model for SAH study is highlighted and presents the challenges and opportunities of this model for future SAH applications. PMID:24076160
Is the Sky the Limit to Education Improvement?

ERIC Educational Resources Information Center

Schleicher, Andreas

2011-01-01

International educational benchmarks make disappointing reading for Americans, but they also indicate a way forward. PISA results show strong performance is possible. Whether in Japan, Korea, Finland or Canada, many countries display strong overall performance and show socioeconomic background doesn't determine results. Some countries show that…
Current developments in the treatment of early-stage classical Hodgkin lymphoma.

PubMed

Borchmann, Sven; von Tresckow, Bastian; Engert, Andreas

2016-09-01

After presenting the current treatment recommendations for early-stage Hodgkin lymphoma, we give an overview on recently published clinical trials in this setting. Furthermore, the potential influence of current trials on the treatment of early-stage Hodgkin lymphoma and integration of newly emerging drugs into treatment protocols will be discussed. Trials attempting treatment de-escalation and omission of radiotherapy on the basis of early interim PET-scans have been disappointing so far, but results of some large trials employing this strategy are still awaited. In contrast, a more defensive strategy of starting treatment with less aggressive doxorubicine, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy and intensifying treatment in early interim PET-positive patients has shown encouraging results. New drugs such as brentuximab vedotin and immune checkpoint inhibitors have shown promising results in relapsed and refractory Hodgkin lymphoma. Clinical trials of brentuximab vedotin in early-stage Hodgkin lymphoma have been initiated. Additionally, biomarker-based treatment de-escalation might be a possible route for future improvements. The challenge for future clinical research in early-stage Hodgkin lymphoma is to continue to cure the majority of patients with first-line treatment while reducing long-term toxicity. New strategies to achieve that goal are currently being developed and will further refine treatment of early-stage Hodgkin lymphoma.
New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response

PubMed Central

Bartelink, IH; Zhang, N; Keizer, RJ; Strydom, N; Converse, PJ; Dooley, KE; Nuermberger, EL

2017-01-01

Abstract Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse‐to‐human translational pharmacokinetics (PKs) – pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species‐specific protein binding, drug‐drug interactions, and patient‐specific pathology. Simulations of recent trials testing 4‐month regimens predicted 65% (95% confidence interval [CI], 55–74) relapse‐free patients vs. 80% observed in the REMox‐TB trial, and 79% (95% CI, 72–87) vs. 82% observed in the Rifaquin trial. Simulation of 6‐month regimens predicted 97% (95% CI, 93–99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials. PMID:28561946
Targeting targeted agents: open issues for clinical trial design.

PubMed

Bria, Emilio; Di Maio, Massimo; Carlini, Paolo; Cuppone, Federica; Giannarelli, Diana; Cognetti, Francesco; Milella, Michele

2009-05-22

Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.
Communicating microarray results of uncertain clinical significance in consultation summary letters and implications for practice.

PubMed

Paul, Jean Lillian; Pope-Couston, Rachel; Wake, Samantha; Burgess, Trent; Tan, Tiong Yang

2016-01-01

Letter-writing is an integral practice for genetic health professionals. In Victoria, Australia, patients with a chromosomal variant of uncertain clinical significance (VUS) referred to a clinical geneticist (CG) for evaluation receive consultation summary letters. While communication of uncertainty has been explored in research to some extent, little has focused on how uncertainty is communicated within consultation letters. We aimed to develop a multi-layered understanding of the ways in which CGs communicate diagnostic uncertainty in consultation summary letters. We used theme-oriented discourse analysis of 49 consultation summary letters and thematic analysis of a focus group involving eight CGs. Results showed that CGs have become more confident in their description of VUS as 'contributing factors' to patients' clinical features, but remain hesitant to assign definitive causality. CGs displayed strong epistemic stance when discussing future technological improvements to provide hope and minimise potentially disappointing outcomes for patients and families. CGs reported feeling overwhelmed by their workload associated with increasing numbers of patients with VUS, and this has led to a reduction in the number of review appointments offered over time. This study provides a rich description of the content and process of summary letters discussing VUS. Our findings have implications for letter-writing and workforce management. Furthermore, these findings may be of relevance to VUS identified by genomic sequencing in clinical practice.

Hydroxycarbamide-Induced Changes in E/beta Thalassemia Red Blood Cells

PubMed Central

Sylvia, Singer T.; Elliott, Vichinsky; Sandra, Larkin; Nancy, Olivieri; Nancy, Sweeters; Frans, Kuypers A.

2010-01-01

In thalassemia, fetal hemoglobin (HbF) augmentation with hydroxycarbamide (also known as hydroxyurea) is not always successful. The expected parallel effects on RBC membrane deformability, cell hydration and membrane phospholipid organization, all important for extending RBC life span and increasing Hb, have been infrequently examined. We analyzed these characteristics in 15 non-transfused E/β 0 thalassemia patients treated with HU (mean 10.2 months). Membrane deformability and cell hydration mildly improved in association with increased HbF levels approaching statistical significance (r = 0.51, p=0.06). All measures improved considerably splenectomized patients. These findings underscore the disappointing results of hydroxyurea treatment in clinical trials; and the importance of examining the effect on red cell characteristics for the development and understanding of HbF-enhancing agents. PMID:18821710
Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

PubMed Central

Lemmens, Katrien; Vrints, Christiaan J.

2017-01-01

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF. PMID:28706575
Clinical challenges in thyroid disease: Time for a new approach?

PubMed

Juby, A G; Hanly, M G; Lukaczer, D

2016-05-01

Thyroid disease is common, and the prevalence is rising. Traditional diagnosis and monitoring relies on thyroid stimulating hormone (TSH) levels. This does not always result in symptomatic improvement in hypothyroid symptoms, to the disappointment of both patients and physicians. A non-traditional therapeutic approach would include evaluation of GI function as well as a dietary history and micronutrient evaluation. This approach also includes assessment of thyroid peroxidase (TPO) antibodies, T3, T4, and reverse T3 levels, and in some cases may require specific T3 supplementation in addition to standard T4 therapy. Both high and low TSH levels on treatment are associated with particular medical risks. In the case of high TSH this is primarily cardiac, whereas for low TSH it is predominantly bone health. This article discusses these important clinical issues in more detail, with some practical tips especially for an approach to the "non-responders" to the current traditional therapeutic approach. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Fibrocytes: A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression.

PubMed

Goto, Hisatsugu; Nishioka, Yasuhiko

2017-12-29

An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed.
Pay-for-Performance: Disappointing Results or Masked Heterogeneity?

PubMed Central

Markovitz, Adam A.; Ryan, Andrew M.

2018-01-01

Research on the effects of pay-for-performance (P4P) in health care indicates largely disappointing results. This central finding, however, may mask important heterogeneity in the effects of P4P. We conducted a literature review to assess whether hospital and physician performance in P4P varied by patient and catchment area factors, organizational and structural capabilities, and P4P program characteristics. Several findings emerged: organizational size, practice type, teaching status, and physician age and gender modify performance in P4P. For physician practices and hospitals, a higher proportion of poor and minority patients is consistently associated with worse performance. Other theoretically influential characteristics – including information technology and staffing levels – yield mixed results. Inconsistent and contradictory effects of bonus likelihood, bonus size, and marginal costs on performance in P4P suggest organizations have not responded strategically to financial incentives. We conclude that extant heterogeneity in the effects of P4P does not fundamentally alter current assessments about its effectiveness. PMID:26743502
Management of hidradenitis suppurativa in pregnancy.

PubMed

Perng, Powell; Zampella, John G; Okoye, Ginette A

2017-05-01

Hidradenitis suppurativa is a debilitating inflammatory skin disease with a chronic course and often disappointing response to treatment. Though a minority of persons (20%) reports symptom remission during pregnancy, the vast majority experiences no relief (72%), and few experience clinical deterioration (8%). Disease flares are also observed post-partum. The pathophysiological basis for pregnancy-associated fluctuations in clinical status is currently unknown. Because most women with HS require ongoing management throughout pregnancy, it is important to evaluate the suitability and safety of current treatment options for pregnant women. The following review will outline current management strategies for HS and their compatibility with pregnancy and lactation. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Student-Faculty Interactions about Disappointing Grades: Application of the Goals-Plans-Actions Model and the Theory of Planned Behavior

ERIC Educational Resources Information Center

Henningsen, Mary Lynn Miller; Valde, Kathleen S.; Russell, Gregory A.; Russell, Gregory R.

2011-01-01

The goals-plans-actions model and the theory of planned behavior were used to predict what lead to students having a conversation about a disappointing grade with a faculty member. Participants (N = 130) completed two surveys. In the first survey, participants completed measures of primary and secondary goals, planning, decision to engage,…
A chance to stop and breathe: participants’ experiences in the North American Opiate Medication Initiative clinical trial

PubMed Central

2014-01-01

Background The North American Opiate Medication Initiative (NAOMI) clinical trial compared the effectiveness of injectable diacetylmorphine (DAM) or hydromorphone (HDM) to oral methadone maintenance treatment (MMT). This study aimed to determine participants’ perceptions of treatment delivered in NAOMI. Methods A qualitative sub-study was conducted with 29 participants (12 female): 18 (62.1%) received injectable DAM or HDM and 11 (37.9%) received MMT. A phenomenological theoretical framework was used. Semi-structured interviews were audio-recorded and transcribed verbatim. A thematic analysis was used over successive phases and was driven by the semantic meanings of the data. Results Participants receiving injectable medications suggested that the supervised delivery model was stringent but provided valuable stability to their lives. Females discussed the adjustment required for the clinical setting, while males focused on the challenging clinic schedule and its impact on employment abilities. Participants receiving MMT described disappointment with being randomized to this treatment; however, positive aspects, including the quick titration time and availability of auxiliary services, were also discussed. Conclusion Treatment with injectable DAM (or HDM) is preferred by participants and considered effective in reducing the burden of opioid dependency. Engaging patients in research regarding their perceptions of treatment provides a comprehensive assessment of treatment needs and barriers. Clinical trial registration NCT00175357 PMID:25262567
A UML approach to process modelling of clinical practice guidelines for enactment.

PubMed

Knape, T; Hederman, L; Wade, V P; Gargan, M; Harris, C; Rahman, Y

2003-01-01

Although clinical practice guidelines (CPGs) have been suggested as a means of encapsulating best practice in evidence-based medical treatment, their usage in clinical environments has been disappointing. Criticisms of guideline representations have been that they are predominantly narrative and are difficult to incorporate into clinical information systems. This paper analyses the use of UML process modelling techniques for guideline representation and proposes the automated generation of executable guidelines using XMI. This hybrid UML-XMI approach provides flexible authoring of guideline decision and control structures whilst integrating appropriate data flow. It also uses an open XMI standard interface to allow the use of authoring tools and process control systems from multiple vendors. The paper first surveys CPG modelling formalisms followed by a brief introduction to process modelling in UMI. Furthermore, the modelling of CPGs in UML is presented leading to a case study of encoding a diabetes mellitus CPG using UML.
Multiple sclerosis decreases explicit counterfactual processing and risk taking in decision making.

PubMed

Simioni, Samanta; Schluep, Myriam; Bault, Nadège; Coricelli, Giorgio; Kleeberg, Joerg; Du Pasquier, Renaud A; Gschwind, Markus; Vuilleumier, Patrik; Annoni, Jean-Marie

2012-01-01

Deficits in decision making (DM) are commonly associated with prefrontal cortical damage, but may occur with multiple sclerosis (MS). There are no data concerning the impact of MS on tasks evaluating DM under explicit risk, where different emotional and cognitive components can be distinguished. We assessed 72 relapsing-remitting MS (RRMS) patients with mild to moderate disease and 38 healthy controls in two DM tasks involving risk with explicit rules: (1) The Wheel of Fortune (WOF), which probes the anticipated affects of decisions outcomes on future choices; and (2) The Cambridge Gamble Task (CGT) which measures risk taking. Participants also underwent a neuropsychological and emotional assessment, and skin conductance responses (SCRs) were recorded. In the WOF, RRMS patients showed deficits in integrating positive counterfactual information (p<0.005) and greater risk aversion (p<0.001). They reported less negative affect than controls (disappointment: p = 0.007; regret: p = 0.01), although their implicit emotional reactions as measured by post-choice SCRs did not differ. In the CGT, RRMS patients differed from controls in quality of DM (p = 0.01) and deliberation time (p = 0.0002), the latter difference being correlated with attention scores. Such changes did not result in overall decreases in performance (total gains). The quality of DM under risk was modified by MS in both tasks. The reduction in the expression of disappointment coexisted with an increased risk aversion in the WOF and alexithymia features. These concomitant emotional alterations may have implications for better understanding the components of explicit DM and for the clinical support of MS patients.
The Therapeutic School.

ERIC Educational Resources Information Center

Rice, John Steadman

2002-01-01

Contributes to the recent research on specific institutional carriers of the therapeutic culture, such as the state, the corporation, and the self- help movement, defining therapeutic discourse and discussing the therapeutic ethic, the therapeutic school, schools of education and their critics, and disappointing results of therapeutic schooling.…
Is LASIK for Me? A Patient's Guide to Refractive Surgery

MedlinePlus

... whether LASIK would be appropriate for you are: • dry eye syndrome . If dry eye is left untreated prior to surgery, patients may be disappointed with their LASIK results. If dry eye is diagnosed and adequately treated before surgery, you ...
Poland Country Analysis Brief

EIA Publications

2016-01-01

Poland is the second largest coal producer in Europe, behind Germany. Poland produces small quantities of crude oil and natural gas and it is a net oil and natural gas importer. The country contains shale resources, but companies exploring for economically recoverable volumes have had disappointing results.
Passenger vehicles sustain huge damage in 5 Mph tests

DOT National Transportation Integrated Search

2000-04-15

Seventeen new cars, all 1999 and 2000 models, turned in mostly disappointing results in 5 mph crash tests conducted to assess how well the bumpers resist costly damage in the kinds of impacts that frequently occur in commuter traffic and parking lots...
Obama and the "Arab Spring": Desire, Hope and the Manufacture of Disappointment. Implications for a Transformative Pedagogy

ERIC Educational Resources Information Center

Roberts, Lorna; Schostak, John

2012-01-01

For a period, in the run up to the election (2007-2008) and the months after the election, the name "Obama" signified hope for millions, not just in America but across the world. As the hope turned to disappointment, the financial crisis deepened and the Arab Spring renewed a call for a "humanity" that could transcend the differences of nations…
The role of nutritional support in the physical and functional recovery of critically ill patients: a narrative review.

PubMed

Bear, Danielle E; Wandrag, Liesl; Merriweather, Judith L; Connolly, Bronwen; Hart, Nicholas; Grocott, Michael P W

2017-08-26

The lack of benefit from randomised controlled trials has resulted in significant controversy regarding the role of nutrition during critical illness in terms of long-term recovery and outcome. Although methodological caveats with a failure to adequately appreciate biological mechanisms may explain these disappointing results, it must be acknowledged that nutritional support during early critical illness, when considered alone, may have limited long-term functional impact.This narrative review focuses specifically on recent clinical trials and evaluates the impact of nutrition during critical illness on long-term physical and functional recovery.Specific focus on the trial design and methodological limitations has been considered in detail. Limitations include delivery of caloric and protein targets, patient heterogeneity, short duration of intervention, inappropriate clinical outcomes and a disregard for baseline nutritional status and nutritional intake in the post-ICU period.With survivorship at the forefront of critical care research, it is imperative that nutrition studies carefully consider biological mechanisms and trial design because these factors can strongly influence outcomes, in particular long-term physical and functional outcome. Failure to do so may lead to inconclusive clinical trials and consequent rejection of the potentially beneficial effects of nutrition interventions during critical illness.
Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration.

PubMed

Teixeira-da-Cunha, Mariana G A; Gomes, Rachel N; Roehrs, Nathassia; Bozza, Fernando A; Prescott, Stephen M; Stafforini, Diana; Zimmerman, Guy A; Bozza, Patricia T; Castro-Faria-Neto, Hugo C

2013-01-01

Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.
Counterinsurgency in Vietnam, Afghanistan, and Iraq: A Critical Analysis

DTIC Science & Technology

2014-05-01

took advantage of the corruption and inefficiency of the government to recruit the proletariat for membership in the trade unions.18...which might end with disappointing results. Intergrity is an issue when dealing with the large quantities of emergency aid and funding available to
Old Wine into New Bottles.

ERIC Educational Resources Information Center

Crandall, G. Douglas

1997-01-01

Discusses how traditional lab exercises can be converted into investigative exercises. Describes an exercise on seed germination that has students design their own experiments based on their initial results. Involves students in the scientific process and allows them to experience the joys and disappointments of experimental work. (JRH)
[The effect of goal framing on the activation of affective representations].

PubMed

Takehashi, Hiroki; Karasawa, Kaori

2007-10-01

Guided by regulatory focus theory, this study examined the effects of goal framing on the subjective experience of affect and the accessibility of affective representations. Study I examined lay persons' beliefs concerning the relationship between goal framing and certain kinds of affective experiences. The results indicated that a promotion focus was associated with happiness and disappointment, whereas a prevention focus was associated with relaxation and tension. Study 2 examined the effect of goal framing on the activation of affective representations, and found that a promotion focus activated both gain-related representations (happy and disappointment) and loss-related representations (relaxation and tension), whereas a prevention focus activated only loss-related representations. These results suggest that goal framing activates particular affective representations, and the activated affective representations may influence the interpretation of positive or negative experiences. The discussion considered the function of the activation of affective representations as a mediator between goal framing and its cognitive and behavioral consequences.

Policy review: Japan-Philippines Economic Partnership Agreement (JPEPA)--analysis of a failed nurse migration policy.

PubMed

Yagi, Nozomi; Mackey, Tim K; Liang, Bryan A; Gerlt, Lorna

2014-02-01

In 2008, the bilateral Japan-Philippines Economic Partnership Agreement took effect. Contained within this regional free trade agreement are unique provisions allowing exchange of Filipino nurses and healthcare workers to work abroad in Japan. Japan's increasing need for healthcare workers due to its aging demographic and the Philippines need for economic development could have led to shared benefits under the Japan-Philippines Economic Partnership Agreement. However, 4 years following program implementation, results have been disappointing, e.g., only 7% of candidates passing the programs requirements since 2009. These disappointing results represent a policy failure within the current Japan-Philippines Economic Partnership Agreement framework, and point to the need for reform. Hence, amending the current Japan-Philippines Economic Partnership Agreement structure by potentially adopting a USA based approach to licensure examinations and implementing necessary institutional and governance reform measures may be necessary to ensure beneficial healthcare worker migration for both countries. Copyright © 2013 Elsevier Ltd. All rights reserved.
Advances in Merkel cell carcinoma from a pathologist's perspective.

PubMed

Barksdale, Sarah Kay

2017-10-01

Merkel cell carcinoma (MCC) is a rarely made but potentially devastating diagnosis. While local disease might be cured by surgery and radiotherapy, advanced disease is usually rapidly progressive and fatal. Until very recently, the only approach to metastatic MCC was cytotoxic chemotherapy with results so disappointing that current treatment guidelines discourage its use and recommend clinical trial as a more viable treatment option. Fortunately, recent advances in the understanding of the molecular pathogenesis of this tumour have produced a wide variety of experimental treatments for MCC, some of which are quite promising. The most current information regarding the diagnosis, staging, management of this tumour is briefly presented as well as new insights into the molecular basis of MCC and therapeutic approaches to MCC. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.
Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury.

PubMed

Howard, Randy B; Sayeed, Iqbal; Stein, Donald G

2017-06-01

To date, outcomes for all Phase III clinical trials for traumatic brain injury (TBI) have been negative. The recent disappointing results of the Progesterone for the Treatment of Traumatic Brain Injury (ProTECT) and Study of a Neuroprotective Agent, Progesterone, in Severe Traumatic Brain Injury (SyNAPSe) Phase III trials for progesterone in TBI have triggered considerable speculation about the reasons for the negative outcomes of these two studies in particular and for those of all previous Phase III TBI clinical trials in general. Among the factors proposed to explain the ProTECT III and SyNAPSe results, the investigators themselves and others have cited: 1) the pathophysiological complexity of TBI itself; 2) issues with the quality and clinical relevance of the preclinical animal models; 3) insufficiently sensitive clinical endpoints; and 4) inappropriate clinical trial designs and strategies. This paper highlights three critical trial design factors that may have contributed substantially to the negative outcomes: 1) suboptimal doses and treatment durations in the Phase II studies; 2) the strategic decision not to perform Phase IIB studies to optimize these variables before initiating Phase III; and 3) the lack of incorporation of the preclinical and Chinese Phase II results, as well as allometric scaling principles, into the Phase III designs. Given these circumstances and the exceptional pleiotropic potential of progesterone as a TBI (and stroke) therapeutic, we are advocating a return to Phase IIB testing. We advocate the incorporation of dose and schedule optimization focused on lower doses and a longer duration of treatment, combined with the addressing of other potential trial design problems raised by the authors in the recently published trial results.
A New Paradigm to Address Bid Protests

DTIC Science & Technology

2010-08-02

A two- player game model is being developed by members of the NPS Protest Project team that allows for shared awards (split buys). Split-buy remedies...11 - k^s^i=mlpqdo^ar^qb=p`elli= = The literature generally focuses on two players : a disappointed bidder20 and the government. In fact, the...government can be broken into several distinct players , each of which might expect a challenge from a disappointed bidder: procurement officials (POs) and
Sub-Saharan Africa Report. No. 2824.

DTIC Science & Technology

1983-07-25

certain amount of disappointment was felt within some of the political groups. This disappointment affected the MONIMA K movement first. This group hoped...to repeat its achievements of November 1982 at the time of the presidential elections. A similar feeling affects the AKFM which, in a striking...most seriously affected by drought. "In continuing this long term effort I can assure you that Mali does not stand alone and that it will continue to
Dupuytren disease: on our way to a cure?

PubMed

Degreef, Ilse; De Smet, Luc

2013-06-01

Despite its high prevalence, the clinical presentation and severity of Dupuytren disease is extremely variable. The disease features a broad spectrum of symptoms, from simple nodules without the slightest clinical impact towards an extremely disabling form requiring multiple surgical procedures, sometimes even partial hand amputations. Recurrence after surgery is considered a failure for both patient and surgeon, but its definition is vague. The term 'recontracture' was coined by a patient and reflects the disappointment of recurrent disease. Wether or not a treatment option will insure a definite result, may depend more on the severity of the disease, which is patient specific, than on the treatment method itself. If a patient presents with Dupuytren disease, one should not merely evaluate his hands. Different clinical and personal history features may uncover a severe fibrosis diathesis and both correct information to the patient and an individualized treatment plan are needed. In the near future, a simple genetic test may help to identify patients at risk. Similar to the evolving knowledge and treatment modalities seen in rheumatoid arthritis, treatment of Dupuytren disease is likely to advance in the direction of disease control with pharmacotherapy and single shot minimal invasive enzymatic fasciotomy with collagenase to correct established contractures.
The State of Middle Eastern Studies.

ERIC Educational Resources Information Center

Lewis, Bernard

1979-01-01

After tracing European study of the Middle East from medieval times, the author concludes that, for all the money and effort being expended in English and American universities, results are disappointing. He notes problems of partisanship, influence of outside financial benefactors, poor academic standards, the language difficulty, and…
On the Death and Transfiguration of Leadership Training.

ERIC Educational Resources Information Center

Fiedler, Fred E.

Empirical research shows that neither leadership training nor experience increases organizational performance. These disappointing results can be explained by the Contingency Model. This theory postulates that task motivated low esteem for the Least Preferred Coworker (LPC) leaders perform best in very favorable and unfavorable situations while…
Leveraging Failure in Design Research

ERIC Educational Resources Information Center

Lobato, Joanne; Walters, C. David; Hohensee, Charles; Gruver, John; Diamond, Jaime Marie

2015-01-01

Even in the resource-rich, more ideal conditions of many design-based classroom interventions, unexpected events can lead to disappointing results in student learning. However, if later iterations in a design research study are more successful, the previous failures can provide opportunities for comparisons to reveal subtle differences in…
Endoscopic botox injections in therapy of refractory gastroparesis

PubMed Central

Ukleja, Andrew; Tandon, Kanwarpreet; Shah, Kinchit; Alvarez, Alicia

2015-01-01

Gastroparesis (GP) is a common disease seen in gastroenterology practice particularly in western countries, and it may be underdiagnosed. The available drug therapies for this condition are quite disappointing. Botulinum toxin type A (BT) has been found to be effective therapy in various spastic disorders of smooth muscle of gastrointestinal tract. However, the benefits of BT injections in GP have been unclear. Several retrospective and open label studies have shown clinical advantages of intrapyloric Botulinum toxin type A injections, while two small randomized trials did not show positive results. Therefore, the available published studies yielded conflicting results leading to fading out of botox therapy for GP. We recognize possible clinical benefit of BT injections without any disadvantages of this treatment. We are calling for revisiting the endoscopy guided botox therapy in refractory GP. In this review we discuss important features of these studies pointing out differences in results among them. Differences in patient selection, doses and method of administration of botox toxin in the prior studies may be the cause of conflicting results. The mechanism of action, indications, efficacy and side-effects of BT are reviewed. Finally, we recognize limited evidence to recommend BT in GP and calling attention for future research in this field since no advances in drug management had been made in the last two decades. PMID:26191343
Investigational Antibody-Drug Conjugates for Treatment of B-lineage Malignancies.

PubMed

Herrera, Alex F; Molina, Arturo

2018-05-10

Antibody-drug conjugates (ADCs) are tripartite molecules consisting of a monoclonal antibody, a covalent linker, and a cytotoxic payload. ADC development has aimed to target the specificity inherent in antigen-antibody interactions to deliver potent cytotoxins preferentially to tumor cells and maximize antitumor activity and simultaneously minimize off-target toxicity. The earliest ADCs provided disappointing results in the clinic; however, the lessons learned regarding the need for human or humanized antibodies, more stable linkers, and greater potency payloads led to improved ADCs. Three ADCs, gemtuzumab ozogamicin, brentuximab vedotin (BV), and inotuzumab ozogamicin, have been approved for hematologic malignancies. Site-specific conjugation methods have now resulted in a new generation of more uniform, molecularly defined ADCs. These are expected to display improved in vivo properties and have recently entered the clinic. We reviewed investigational ADCs currently in clinical testing for the treatment of B-cell lineage malignancies, including leukemias, lymphomas, and multiple myeloma. The rationales for antigen targeting, data reported to date, current trial status, and preclinical results for several newer ADCs expected to enter first-in-human studies are presented. Owing to the large number of ongoing and reported BV clinical studies, only the studies of BV for diffuse large B-cell lymphoma and those combining BV with checkpoint inhibitors in B-lineage malignancies have been reviewed. With > 40 ongoing clinical trials and 7 investigational ADCs already having advanced to phase II studies, the role of ADCs in the armamentarium for the treatment of B-lineage malignancies continues to be elucidated. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Current understanding of interactions between nanoparticles and the immune system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dobrovolskaia, Marina A., E-mail: marina@mail.nih.

2016-05-15

The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nanoparticle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure–activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guidemore » safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle–immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15 years of research on the immunotoxicity of engineered nanomaterials. - Graphical abstract: API — active pharmaceutical ingredient; NP — nanoparticles; PCP — physicochemical properties, CARPA — complement activation-related pseudoallergy, ICH — International Conference on Harmonization. Display Omitted - Highlights: • Achievements, disappointments and lessons learned over past decade are reviewed. • Areas in focus include characterization, immunotoxicity and utility in drug delivery. • Future direction focusing on mechanistic immunotoxicity studies is proposed.« less
Spontaneous regulation of emotions in preschool children who stutter: preliminary findings.

PubMed

Johnson, Kia N; Walden, Tedra A; Conture, Edward G; Karrass, Jan

2010-12-01

Emotional regulation of preschool children who stutter (CWS) and children who do not stutter (CWNS) was assessed through use of a disappointing gift (DG) procedure (P. M. Cole, 1986; C. Saarni, 1984, 1992). Participants consisted of 16 CWS and CWNS (11 boys and 5 girls in each talker group) who were 3 to 5 years of age. After assessing each child's knowledge of display rules about socially appropriate expression of emotions, the authors asked the children to participate in a DG procedure. The children received a desirable gift preceding the first free-play task and a disappointing gift preceding a second free-play task. Dependent variables consisted of participants' positive and negative expressive nonverbal behaviors exhibited during receipt of a desirable gift and disappointing gift as well as conversational speech disfluencies exhibited following receipt of each gift. Findings indicated that CWS and CWNS exhibited no significant differences in amount of positive emotional expressions after receiving the desired gift; however, CWS--when compared with CWNS--exhibited more negative emotional expressions after receiving the undesirable gift. Furthermore, CWS were more disfluent after receiving the desired gift than after receiving the disappointing gift. Ancillary findings also indicated that CWS and CWNS had equivalent knowledge of display rules. Findings suggest that efforts to concurrently regulate emotional behaviors and that speech disfluencies may be problematic for preschool-age CWS.
The contribution of clinical neurophysiology to the comprehension of the tension-type headache mechanisms.

PubMed

Rossi, Paolo; Vollono, Catello; Valeriani, Massimiliano; Sandrini, Giorgio

2011-06-01

So far, clinical neurophysiological studies on tension-type headache (TTH) have been conducted with two main purposes: (1) to establish whether some neurophysiological parameters may act as markers of TTH, and (2) to investigate the physiopathology of TTH. With regard to the first point, the present results are disappointing, since some abnormalities found in TTH patients may be frequently observed also in migraineurs. On the other hand, clinical neurophysiology has played an important role in the debate about the pathogenesis of TTH. Studies on the exteroceptive suppression of the temporalis muscle contraction have detected a dysfunction of the brainstem excitability and of its suprasegmental control. A similar conclusion has been reached by using the trigeminocervical reflexes, whose abnormalities in TTH have suggested a reduced inhibitory activity of brainstem interneurons, reflecting abnormal endogenous pain control mechanisms. It is interesting that the neural excitability abnormality in TTH seems to be a generalized phenomenon, not limited to the cranial districts. Defective DNIC-like mechanisms have indeed been evidenced also in somatic districts by nociceptive flexion reflex studies. Unfortunately, most neurophysiological studies on TTH are marred by serious methodological flaws, which should be avoided in future researches, in order to better clarify the TTH mechanisms. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Effect of Lecture Instruction on Student Performance on Qualitative Questions

ERIC Educational Resources Information Center

Heron, Paula R. L.

2015-01-01

The impact of lecture instruction on student conceptual understanding in physics has been the subject of research for several decades. Most studies have reported disappointingly small improvements in student performance on conceptual questions despite direct instruction on the relevant topics. These results have spurred a number of attempts to…
Can We Succeed in Teaching Business Students to Write Effectively?

ERIC Educational Resources Information Center

Pittenger, Khushwant K. S.; Miller, Mary C.; Allison, Jesse

2006-01-01

This article presents the results of a study where business students' writing skills were assessed using an external objective measure in a business communication course. The student performance was disappointing before instructor intervention. After the intervention, student performance improved noticeably. The implications of the study are…
Perry Pinyon Pines Protection Project

Treesearch

Daniel McCarthy

2012-01-01

Fuel reduction treatments around pinyon pine trees began as a simple project but ended in something more complex, enjoyable, and rewarding. The project eventually led to pinyon species (Pinus monophylla and P. quadrifolia) reforestation efforts, something that has been tried in the past with disappointing results. The Perry Pinyon Pines Protection Project and current...
"No Effects" Studies Raising Eyebrows

ERIC Educational Resources Information Center

Viadero, Debra

2009-01-01

Like a steady drip from a leaky faucet, the experimental studies being released this school year by the federal Institute of Education Sciences are mostly producing the same results: "No effects," "No effects," "No effects." The disappointing yield is prompting researchers, product developers, and other experts to question the design of the…
Evaluation of the Teaching American History Program

ERIC Educational Resources Information Center

Humphrey, Daniel C.; Chang-Ross, Christopher; Donnelly, Mary Beth; Hersh, Lauren; Skolnik, Heidi

2005-01-01

Nearly 20 years ago, the first national assessment of student achievement in U.S. history yielded disappointing results. Although policy-makers and researchers expressed great concern about the low scores, the federal government did not undertake large-scale efforts to address poor student performance, and few research dollars were dedicated to…
Juvenile Justice Reform: State Experiences. Criminal Justice Paper #4.

ERIC Educational Resources Information Center

Pierce, Robert; Yondorf, Barbara

Community-based programs in the juvenile justice system present a promising alternative to the disappointing results achieved by large institutional facilities. A diverse group of states has found that intensive, individualized services provided in small, family-like residential settings or in the juvenile's own home yield comparable or reduced…

A Systemically Collaborative Approach to Achieving Equity in Higher Education

ERIC Educational Resources Information Center

Prystowsky, Richard J.

2018-01-01

Colleges and universities have long recognized the need to address inequities affecting students from underrepresented or underserved groups. Despite efforts undertaken by dedicated individuals, large-scale, national change in this area has not been realized. In this article, we address two major factors underlying this disappointing result (the…
Are word-of-mouth communications contributing to a shortage of nephrology nurses?

PubMed

Wolfe, William A

2014-01-01

Nephrology nurse shortages have historically been viewed as a subset of the overall nursing supply in the United States. Not-here-to-fore considered as a contributing factor are the effects of word-of-mouth and Internet-based word-of-mouth communications from nurses who have had disappointing work experiences in hemodialysis clinics. This article discusses the potential effects of word-of-mouse communications and posits that negative word-of-mouse communications may discourage new and experienced nurses from considering the specialty of nephrology nursing, thus contributing to a nephrology nursing shortage.
Parkinson's Disease Gene Therapy: Success by Design Meets Failure by Efficacy

PubMed Central

Bartus, Raymond T; Weinberg, Marc S; Samulski, R. Jude

2014-01-01

Over the past decade, nine gene therapy clinical trials for Parkinson's disease (PD) have been initiated and completed. Starting with considerable optimism at the initiation of each trial, none of the programs has yet borne sufficiently robust clinical efficacy or found a clear path toward regulatory approval. Despite the immediately disappointing nature of the efficacy outcomes in these trials, the clinical data garnered from the individual studies nonetheless represent tangible and significant progress for the gene therapy field. Collectively, the clinical trials demonstrate that we have overcome the major safety hurdles previously suppressing central nervous system (CNS) gene therapy, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, these studies also demonstrated controlled, highly persistent generation of biologically active proteins targeted to structures deep in the human brain. Therefore, a renewed, focused emphasis must be placed on advancing clinical efficacy by improving clinical trial design, patient selection and outcome measures, developing more predictive animal models to support clinical testing, carefully performing retrospective analyses, and most importantly moving forward—beyond our past limits. PMID:24356252
Emerging pathways and future targets for the molecular therapy of pancreatic cancer.

PubMed

Vaccaro, Vanja; Melisi, Davide; Bria, Emilio; Cuppone, Federica; Ciuffreda, Ludovica; Pino, Maria Simona; Gelibter, Alain; Tortora, Giampaolo; Cognetti, Francesco; Milella, Michele

2011-10-01

Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.
Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

DOE PAGES

Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; ...

2015-04-01

In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular,more » the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less
Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Briquez, Priscilla S.; Hubbell, Jeffrey A.; Martino, Mikaël M.

2015-08-01

Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localizationmore » of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less
Nivolumab for the treatment of colorectal cancer.

PubMed

Smith, Kortnye Maureen; Desai, Jayesh

2018-05-24

Despite a variety of therapies for advanced metastatic colorectal cancer being available, the outcomes in this malignancy remain sub-optimal. Immunotherapy has been slow to impact the management of this patient group. Checkpoint inhibitors, such as nivolumab, have had disappointing results when used broadly. However, for the subset of patients with microsatellite unstable colorectal cancer the use of checkpoint inhibitors such as nivolumab appears to be transformative, and will provide a new therapeutic option for patient with advanced disease. Areas covered: Nivolumab gained regulatory approval for the treatment of dMMR/MSI-H metastatic colorectal cancer in mid 2017. The current review will summarize the clinical evidence of checkpoint inhibitors in metastatic colorectal cancer, with a focus on nivolumab. Expert commentary: For patients with dMMR/MSI-H mCRC the use of nivolumab has now been shown to have objective and sustained clinical responses in a pivotal phase II trial. While additional data is limited, the therapeutic role for augmenting an immune response in metastatic colorectal cancer is likely to continue to expand. Further combination trials of nivolumab with immunologic and non-immunologic agents are ongoing.
Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela

In this study, blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular,more » the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less
Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela

Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localizationmore » of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.« less
50 years of hurdles and hope in anxiolytic drug discovery

PubMed Central

Griebel, Guy; Holmes, Andrew

2014-01-01

Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (γ-aminobutyric acid)–benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. PMID:23989795
Nutraceuticals as therapeutic agents for atherosclerosis.

PubMed

Moss, Joe W E; Williams, Jessica O; Ramji, Dipak P

2018-05-01

Atherosclerosis, a chronic inflammatory disorder of medium and large arteries and an underlying cause of cardiovascular disease (CVD), is responsible for a third of all global deaths. Current treatments for CVD, such as optimized statin therapy, are associated with considerable residual risk and several side effects in some patients. The outcome of research on the identification of alternative pharmaceutical agents for the treatment of CVD has been relatively disappointing with many promising leads failing at the clinical level. Nutraceuticals, products from food sources with health benefits beyond their nutritional value, represent promising agents in the prevention of CVD or as an add-on therapy with current treatments. This review will highlight the potential of several nutraceuticals, including polyunsaturated fatty acids, flavonoids and other polyphenols, as anti-CVD therapies based on clinical and pre-clinical mechanism-based studies. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.
Community-based health insurance programmes and the national health insurance scheme of Nigeria: challenges to uptake and integration

PubMed Central

2014-01-01

Background Nigeria has included a regulated community-based health insurance (CBHI) model within its National Health Insurance Scheme (NHIS). Uptake to date has been disappointing, however. The aim of this study is to review the present status of CBHI in SSA in general to highlight the issues that affect its successful integration within the NHIS of Nigeria and more widely in developing countries. Methods A literature survey using PubMed and EconLit was carried out to identify and review studies that report factors affecting implementation of CBHI in SSA with a focus on Nigeria. Results CBHI schemes with a variety of designs have been introduced across SSA but with generally disappointing results so far. Two exceptions are Ghana and Rwanda, both of which have introduced schemes with effective government control and support coupled with intensive implementation programmes. Poor support for CBHI is repeatedly linked elsewhere with failure to engage and account for the ‘real world’ needs of beneficiaries, lack of clear legislative and regulatory frameworks, inadequate financial support, and unrealistic enrolment requirements. Nigeria’s CBHI-type schemes for the informal sectors of its NHIS have been set up under an appropriate legislative framework, but work is needed to eliminate regressive financing, to involve scheme members in the setting up and management of programmes, to inform and educate more effectively, to eliminate lack of confidence in the schemes, and to address inequity in provision. Targeted subsidies should also be considered. Conclusions Disappointing uptake of CBHI-type NHIS elements in Nigeria can be addressed through closer integration of informal and formal programmes under the NHIS umbrella, with increasing involvement of beneficiaries in scheme design and management, improved communication and education, and targeted financial assistance. PMID:24559409
Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

PubMed

Correale, Jorge; Gaitán, María I; Ysrraelit, María C; Fiol, Marcela P

2017-03-01

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
New Therapies in Head and Neck Cancer.

PubMed

Santuray, Rodell T; Johnson, Daniel E; Grandis, Jennifer R

2018-05-01

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent. Copyright © 2018 Elsevier Inc. All rights reserved.
Emerging biological therapies for the treatment of myelodysplastic syndromes.

PubMed

Zeidan, Amer M; Stahl, Maximilian; Komrokji, Rami

2016-09-01

No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure. This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche. Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.
New endocrine therapies for breast cancer.

PubMed

Howell, A; Downey, S; Anderson, E

1996-04-01

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.
Vaccines for cocaine abuse.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Kosten, Thomas R

2009-04-01

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.
Weight management in obese pets: the tailoring concept and how it can improve results.

PubMed

German, Alexander J

2016-10-20

Obesity is now recognised as the most important medical disease in pets worldwide. All current strategies for weight management involve dietary energy restriction with a purpose-formulated diet. Whilst current weight management regimes can be successful, outcomes are often disappointing with the rate of weight loss progressively slowing down as time goes on. Success is most challenging for the most obese dogs and cats that are more likely to discontinue the programme before reaching target weight. To improve outcomes, clinicians must focus carefully on better tailoring programmes, paying particular to setting an appropriate target weight so as to maximise the benefits for the individual. In this opinionated review, the author will discuss findings from recent clinical research studies examining weight management in obese dogs and cats. A strategy for tailoring weight management targets will then be discussed, illustrated with case examples.
Tyrosine kinase inhibitor induced growth factor receptor upregulation enhances the efficacy of near-infrared targeted photodynamic therapy in esophageal adenocarcinoma cell lines.

PubMed

Hartmans, Elmire; Linssen, Matthijs D; Sikkens, Claire; Levens, Afra; Witjes, Max J H; van Dam, Gooitzen M; Nagengast, Wouter B

2017-05-02

Esophageal carcinoma (EC) is a global health problem, with disappointing 5-year survival rates of only 15-25%. Near-infrared targeted photodynamic therapy (NIR-tPDT) is a novel strategy in which cancer-targeted phototoxicity is able to selectively treat malignant cells. In this in vitro report we demonstrate the applicability of antibody-based NIR-tPDT in esophageal adenocarcinoma (EAC), using the phototoxic compounds cetuximab-IRDye700DX and trastuzumab-IRDye700DX, targeting respectively epidermal growth factor receptor 1 (EGFR) and 2 (HER2). Furthermore, we demonstrate that NIR-tPDT can be made more effective by tyrosine kinase inhibitor (TKI) induced growth receptor upregulation. Together, these results unveil a novel strategy for non-invasive EAC treatment, and by pretreatment-induced receptor upregulation its future clinical application may be optimized.
Encoded novel forms of HSP70 or a cytolytic protein increase DNA vaccine potency.

PubMed

Garrod, Tamsin; Grubor-Bauk, Branka; Yu, Stanley; Gargett, Tessa; Gowans, Eric J

2014-01-01

In humans, DNA vaccines have failed to demonstrate the equivalent levels of immunogenicity that were shown in smaller animals. Previous studies have encoded adjuvants, predominantly cytokines, within these vaccines in an attempt to increase antigen-specific immune responses. However, these strategies have lacked breadth of innate immune activation and have led to disappointing results in clinical trials. Damage associated molecular patterns (DAMPs) have been identified as pattern recognition receptor (PRR) agonists. DAMPs can bind to a wide range of PRRs on dendritic cells (DCs) and thus our studies have aimed to utilize this characteristic to act as an adjuvant in a DNA vaccine approach. Specifically, HSP70 has been identified as a DAMP, but has been limited by its lack of accessibility to PRRs in and on DCs. Here, we discuss the promising results achieved with the inclusion of membrane-bound or secreted HSP70 into a DNA vaccine encoding HIV gag as the model immunogen.

Training and capacity building evaluation: Maximizing resources and results with Success Case Method.

PubMed

Medina, L; Acosta-Pérez, E; Velez, C; Martínez, G; Rivera, M; Sardiñas, L; Pattatucci, A

2015-10-01

This article describes the use of Success Case Method (Brinkerhoff, 2003) to evaluate health promotion and public health training programs. The goal of the Office Community Research and Engagement (OCRE) of the Puerto Rico Clinical and Translational Research Consortium (PRCTRC) is to establish a stable and sustainable translational research capacity. Early efforts toward achieving this goal included sponsoring two independent research training programs. A description of the implementation of the five step Success Case Method is presented. Results reveal that SCM would deem both trainings as highly successful, based upon the overall impact of a low number of success cases. However, a traditional summative evaluation would consider this disappointing. Strengths of SCM are discussed. It was concluded that the Success Case Method is a useful and valuable evaluative method for measuring the success of health promotion and public health training initiatives and provides sufficient information for decision-making processes. Copyright © 2015 Elsevier Ltd. All rights reserved.
N-acetylcysteine – passe-partout or much ado about nothing?

PubMed Central

Aitio, Mirja-Liisa

2006-01-01

In experimental studies, the old mucolytic agent N-acetylcysteine (NAC) has had beneficial effects in disorders supposedly linked to oxidative stress. Numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases. NAC added to the conventional therapy of human immunodeficiency virus infection might be of benefit; in respect of chronic obstructive pulmonary disease, systematic reviews and meta-analyses suggested that prolonged treatment with NAC is efficacious, but a recent multicentre study has questioned this. In a large intervention trial on cancer recurrence, NAC was ineffective. NAC infusions have been widely used in acute hepatic failure but convincing evidence of its benefits is lacking. A preliminary study reported that NAC is effective in preventing radiocontrast-induced nephropathy but thereafter highly mixed results have been published, and even meta-analyses disagree on its efficacy. In intensive care NAC has mostly been a disappointment but recently it has ‘given promises’ in surgery with cardiopulmonary bypass. NAC therapy is routine only in paracetamol intoxication. PMID:16390346
Drugs targeting high-density lipoprotein cholesterol for coronary artery disease management.

PubMed

Katz, Pamela M; Leiter, Lawrence A

2012-01-01

Many patients remain at high risk for future cardiovascular events despite levels of low-density lipoprotein cholesterol (LDL-C) at, or below, target while taking statin therapy. Much effort is therefore being focused on strategies to reduce this residual risk. High-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk and is therefore an attractive therapeutic target. Currently available agents that raise HDL-C have only modest effects and there is limited evidence of additional cardiovascular risk reduction on top of background statin therapy associated with their use. It was hoped that the use of cholesteryl ester transfer protein (CETP) inhibitors would provide additional benefit, but the results of clinical outcome studies to date have been disappointing. The results of ongoing trials with other CETP inhibitors that raise HDL-C to a greater degree and also lower LDL-C, as well as with other emerging therapies are awaited. Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences

PubMed Central

Lozano-Maneiro, Luz; Puente-García, Adriana

2015-01-01

Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID:26569322
Inductive discipline, parental expression of disappointed expectations, and moral identity in adolescence.

PubMed

Patrick, Renee B; Gibbs, John C

2012-08-01

Within the fields of socialization and moral development, the relationship of parenting to adolescents' sense of morality and self has been understudied. This study investigated the relationships between perceived parental disciplinary techniques and moral identity among early and middle adolescents. Participants included 93 (54% female) 5th, 8th and 10th graders, as well as their mothers. Students completed self-report measures concerning their mothers' disciplinary techniques and moral self-concept; mothers reported specifically on parental discipline frequency. The parental discipline measure was structured in terms of Hoffman's typology of induction, love withdrawal, and power assertion. Adolescents reported the frequency of their mothers' disciplinary techniques, as well as their perceptions (fairness or appropriateness evaluations, emotional reactions) concerning their mothers' most frequently used technique. Parental induction (orienting the transgressor to the plight of the victim) and expression of disappointed expectations were viewed as more appropriate and responded to with more positive emotion and guilt relative to other disciplinary techniques (e.g., power assertion). In addition, parental use of inductive discipline (including parental disappointment) during the adolescent years related to higher moral identity, defined in terms of the ascription of specifically moral (e.g., fair, kind) over non-moral (e.g., athletic, smart) qualities to the self. In contrast, love withdrawal and power assertion did not relate to moral identity. The findings suggest that parental expression of disappointed expectations, especially when perceived favorably, plays an important role in the formation of moral identity during the adolescent years.
Dreams and disappointments regarding nursing: Student nurses' reasons for attrition and retention. A qualitative study design.

PubMed

Ten Hoeve, Yvonne; Castelein, Stynke; Jansen, Gerard; Roodbol, Petrie

2017-07-01

In the Netherlands, hundreds of students register annually for a nursing programme, but not all of these students manage to complete their training. The main aim of this study was to examine which factors affect student nurses' decision to leave or complete their programme. The study used an exploratory descriptive design, employing a qualitative phenomenological approach. Student nurses (n=17) at the beginning of their third year of the four-year Bachelor's programme. Data were collected at four Universities of Applied Sciences in the Netherlands, from December 2013 to January 2014. Semi-structured interviews were used to collect the data, using an interview guide. The main reasons for students to become nurses were the caring aspect, personal experiences with healthcare, role models in their immediate environment, and job opportunities. They had both altruistic and professional perceptions of their profession. Reasons for attrition were strongly related to the training programme and to their clinical placements, in particular the perceived lack of support from mentors and team. Feelings of being welcomed and working in a nice team proved to be more important reasons for completing the programme than the specific clinical field. Student nurses started their studies with many dreams, such as caring for people and having the opportunity to deliver excellent nursing care. When their expectations were not met, their dreams became disappointments which caused them to consider stopping and even to leave (attrition). The role of lecturers and mentors seems invaluable in protecting and guiding students through their programme and placements. Optimal cooperation between lecturers and mentors is of paramount importance to retain student nurses in their training programmes. Copyright © 2017 Elsevier Ltd. All rights reserved.
Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA)

PubMed Central

Tijono, S M; Guo, K; Henare, K; Palmer, B D; Wang, L-C S; Albelda, S M; Ching, L-M

2013-01-01

Background: Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models. Methods: Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts. Results: Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems. Conclusion: Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds. PMID:23481185
Connecting Research to Teaching: Integrated Curricula and Preparation for College Mathematics

ERIC Educational Resources Information Center

Post, Thomas R.; Monson, Debra S.; Andersen, Edwin; Harwell, Michael R.

2012-01-01

In the early 1990s, after a long series of disappointing results on national and international mathematics achievement tests the National Science Foundation (NSF) funded the development of thirteen complete mathematics programs at the elementary school, middle school, and secondary school levels. Many teachers were quite happy with the new…
Flawed Implementation or Inconsistent Logics? Lessons from Higher Education Reform in Ukraine

ERIC Educational Resources Information Center

Shaw, Marta A.

2013-01-01

This article investigates two competing explanations of why reforms associated with the Bologna process brought disappointing results in Ukraine. The lack of anticipated benefits from the reforms may stem either from a flawed implementation of the Bologna process, or from more fundamental differences between the models of higher education…
Drivers and Effects of Enterprise Resource Planning Post-Implementation Learning

ERIC Educational Resources Information Center

Chang, Hsiu-Hua; Chou, Huey-Wen

2011-01-01

The use of enterprise resource planning (ERP) systems has grown enormously since 1990, but the failure to completely learn how to use them continues to produce disappointing results. Today's rapidly changing business environment and the integrative applications of ERP systems force users to continuously learn new skills after ERP implementation.…
Getting to Teacher Ownership: How Schools Are Creating Meaningful Change

ERIC Educational Resources Information Center

Saunders, Marissa; Alcantara, Vianna; Cervantes, Laura; Del Razo, Jaime; Lopez, Ruth; Perez, Wendy

2017-01-01

Improving student learning in our country's highest need schools is and endeavor that is challenging, complicated, and imperative. The major school reform efforts of the last few decades have largely failed to influence student achievement or to impact the ever-widening achievement or opportunity gap. These disappointing results have led…
Conditions and Constraints of Sustainable Innovative Pedagogical Practices Using Technology

ERIC Educational Resources Information Center

Tong, K. P.; Trinidad, S. G.

2005-01-01

Like many other countries, Hong Kong Special Administrative Region Government has invested heavily in the computer facilities of schools. It is expected that by using ICT, the quality of education will be enhanced through a paradigm shift in school pedagogical practices. However, some educational innovations resulted in disappointing outcomes and…
The Diploma Qualification in England: An Avoidable Failure?

ERIC Educational Resources Information Center

Isaacs, Tina

2013-01-01

In 2005, the UK government introduced new vocationally related diploma qualifications. Two-year programs were examined in the summers of 2010 and 2011; initial government hopes for candidate numbers proved largely ephemeral and results were disappointing. This article explores what happened to the diploma's lofty ambitions using the summer of 2010…
Geologic map of the Cape Disappointment-Naselle River area, Pacific and Wahkiakum counties, Washington

USGS Publications Warehouse

Wells, R.E.

1989-01-01

The Cape Disappointment-Naselle River area is in southwestern Washington at the mouth of the Columbia River. The area encompasses several major estuaries and their adjacent highlands, which reach elevations of about 2,000 feet. Rainfall is abundant and produces heavy vegetation and deep weathering of the bedrock. Natural bedrock exposures are restricted to stream courses along larger drainages, although a network of logging roads provides excellent access to most of the area and widespread, but somewhat ephemeral, exposures of bedrock.
[Posterosuperior impingement of the shoulder in the athlete: results of arthroscopic debridement in 75 patients].

PubMed

Riand, N; Boulahia, A; Walch, G

2002-02-01

The painful shoulder is a well-recognized clinical entity in throwers although the pathogenic mechanisms involved are still debated. In 1991 Walch then Jobe developed the concept of posterosuperior impingement to explain lesions observed arthroscopically. This impingement between the deep aspect of the supraspinatus tendon and the glenoid occurs during loaded arm movements. The purpose of this work was to study the different types of lesions observed arthroscopically and to analyse outcome after arthroscopic debridement. Our series included 75 thrower athletes who had shoulder pain for loaded arm movements. Pain was situated in the dominant shoulder in all cases. Clinically, the Jobe manipulation provoked pain in 52 patents, expression of a supraspinous disorder. After failure of conservative treatment, the patients underwent arthroscopy for assessment and debridement. At the time of arthroscopy, the patients had suffered pain for two years (mean 22.3 months). All 75 patients were seen for clinical and radiological assessment at least two years after arthroscopy. Among the 75 arthroscopies, there were 67 (89%) partial tears involving the deep aspect of the cuff, associated in 90% of the cases with a labral lesion. Tears involved the supraspinatus in 40 cases, the supraspinatus and the infraspinatus in 24 and the infraspinatus alone in three. Eight patients were free of tendon lesions at arthroscopy. There were no full thickness tears. The labrum had a meniscal (45%) or non-meniscal aspect (55%) and appeared normal (18%), fringed (38%) or fissured (52%). The very large majority of the labral fissures were found behind the biceps insertion. Fissures of the labrum were found in front of the biceps insertion in only three cases (slap lesion). Arthroscopy demonstrated glenoid damage (soft cartilage, fissure, abrasion, wear). The humeral head also exhibited lesions of the cartilage facing the insertion of the infraspinatus. At last follow-up (minimum > 2 years), eight patients were very satisfied, 22 were satisfied and 45 were disappointed. Twelve patients had resumed their sports activities at their former level with loaded arm movement and one patient had interrupted all sports activities. At last follow-up, 22 patient had undergone another surgical procedure: 20 derotation osteotomies of the humerus, one anterior stabilization, one acromioplasty. The notion of posterosuperior impingement is increasingly recognized as the cause of pain in thrower athletes. Loaded arm movements produce a physiological contact between the posteriorsuperior edge of the glenoid cavity and the deep aspect of the rotator cuff. Injury results from repeated loaded arm movements in throwers. In our series, all the patients had at least one lesion, either involving the cuff or the labrum. According to the Snyder classification, 80% of the supraspinatus lesions were grade 1 or grade 2. We did not have any full thickness tears. All patients with a normal cuff were found to have a lesion of the posterosuperior labrum. At arthroscopy, dynamic assessment evidenced an impingement between the supraspinatus (or the infraspinatus) and the labrum or the bony edge of the glenoid cavity. Only three patients had a labral lesion anterior to the biceps insertion that could be considered a type 1 or 2 slap lesion. Unlike earlier reports by others, we had disappointing results after debridement: 60% of the patients were disappointed after the procedure and only 40% were satisfied (22 patients) or very satisfied (8 patients). Patient satisfaction depended greatly on the level of sports activity attained after arthroscopy, the eight very satisfied patients had resumed their former level. None of the professional athletes or those competing at the international level were very satisfied with arthroscopic debridement. There was an inverse relationship between level of competition and patient satisfaction after debridement.
U.S. Strategic Interest in the Middle East and Implications for the Army

DTIC Science & Technology

2017-01-01

three of which evolved into civil wars, have altered the landscape. These have resulted in occasional opportunities, such as the effort to build a...the Arab world, though experience indicates that large-scale intervention in such conflicts is likely to produce disappointing results . Army...the Iranian regime to rally people around the flag. As a result , the United States should be cautious in demonstrating support for such progress
Curcumin and Resveratrol in the Management of Cognitive Disorders: What is the Clinical Evidence?

PubMed

Mazzanti, Gabriela; Di Giacomo, Silvia

2016-09-17

A growing body of in vitro and in vivo evidences shows a possible role of polyphenols in counteracting neurodegeneration: curcumin and resveratrol are attractive substances in this regard. In fact, epidemiological studies highlight a neuroprotective effect of turmeric (rhizome of Curcuma longa L.), the main source of curcumin. Moreover, the consumption of red wine, the main source of resveratrol, has been related to a lower risk of developing dementia. In this review, we analyzed the published clinical trials investigating curcumin and resveratrol in the prevention or treatment of cognitive disorders. The ongoing studies were also described, in order to give an overview of the current search on this topic. The results of published trials (five for curcumin, six for resveratrol) are disappointing and do not allow to draw conclusions about the therapeutic or neuroprotective potential of curcumin and resveratrol. These compounds, being capable of interfering with several processes implicated in the early stages of dementia, could be useful in preventing or in slowing down the pathology. To this aim, an early diagnosis using peripheral biomarkers becomes necessary. Furthermore, the potential preventive activity of curcumin and resveratrol should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability and that are well standardized.
Malaria vaccines: the case for a whole-organism approach.

PubMed

Pinzon-Charry, Alberto; Good, Michael F

2008-04-01

Malaria is a significant health problem causing morbidity and mortality worldwide. Vaccine development has been an imperative for decades. However, the intricacy of the parasite's lifecycle coupled with the lack of evidence for robust infection-induced immunity has made vaccine development exceptionally difficult. To review some of the key advances in the field and discuss potential ways forward for a whole-organism vaccine. The authors searched PubMed using the words 'malaria and vaccine'. We searched for manuscripts detailing antigen characterisation and vaccine strategies with emphasis on subunit versus whole-parasite approaches. Abstracts were selected and relevant articles are discussed. The searches were not restricted by language or date. The early cloning of malaria antigens has fuelled rapid development of subunit vaccines. However, the disappointing results of clinical trials have resulted in reappraisal of current strategies. Whole-parasite approaches have re-emerged as an alternative strategy. Immunization using radiation or genetically attenuated sporozoites has been shown to result in sterile immunity and immunization with blood-stage parasites curtailed by antimalarials has demonstrated delayed parasitemia in rodent models as well as in human malaria.
Reverse shoulder arthroplasty in 3 and 4 part proximal humeral fractures in patients aged more than 65 years: Results and complications.

PubMed

Villodre-Jiménez, J; Estrems-Díaz, V; Diranzo-García, J; Bru-Pomer, A

The treatment of 3and 4 part proximal humeral fractures in elderly patients is still controversial. The frequent co-existence of poor quality bone and rotator cuff abnormalities in patients with multiple clinical conditions and with difficulties for physical rehabilitation leads to disappointing clinical results, even when the radiological images are acceptable. To evaluate the clinical, radiological, and functional results in patients over 65 years old with complex proximal humerus fractures treated with reverse shoulder arthroplasty. A prospective review was carried out on 30 patients (26 women and 4 men) with proximal humeral fractures treated with reverse shoulder arthroplasty in our department. The mean age was 74.9 years (SD=6.3), and the mean follow-up was 34.5 months (SD=19.3). Clinical and functional results were acceptable, with a mean forward flexion of 124° and a mean external rotation of 13°. The mean abbreviated Constant abbreviated score was 49.1 (SD=14.1), 27 (SD=6.3) in the UCLA scale, and 32.2 (SD=19.2) in the QuickDASH questionnaire. The large majority (80%) of the patients are pain free, and they do not need medication to do daily activities. The complication rate was 13.3%. We consider that reverse shoulder arthroplasty is a valid option to treat 3and 4 part proximal humeral fractures in elderly patients. The surgical goals should include the anatomical reconstruction of the tuberosities, avoiding enlargement of the operated arm greater than 2cm. Copyright © 2016 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.
The impact assessment of weight loss on an aggressive behavior and satisfaction with the connubial or cohabitation relationship in patients after Roux-en-Y gastric-by-pass surgery performed laparoscopically.

PubMed

Bielecka, Ilona; Osemek, Paweł; Paśnik, Krzysztof

2012-09-01

was an assesment the impact of weight loss in patients undergoing gastric by-pass surgery on an aggressive behavior affecting the satisfaction with the connubial or cohabitation relationship The study included a total number of 100 people (50 people with morbid obesity underwent gastric-bypass surgery and their male or female partners). The study was conducted by using two questionnaires: the Psychological Inventory of Aggression Syndrome-1 authorship by Z.B. Gaś as well as Extinguishes and the Chosen Marriage Questionnaire-2 developed by M. Plop and J. Rostowski The analysis of the results showed the influence of the weight loss on the aggressive behaviour at the examined group. Important differences were shown in the first phase of the examination among the examined group and the control group on scales: emotional self-aggression, the hostility towards surroundings and directed outside aggression. Regression analysis showed a statistical relationship between outward aggression and disappointment, 0.346 p<0.01, intimacy 0.943 p<0.01, and the result of general satisfaction with the relationship 0.832 p<0.05.While self-realization is negatively correlated with a displaced aggression -0.342 p<0.01 and the intermediate one -0.225 p<0.01. Hostility towards the environment correlates positively with intimacy 0.326 p<0.01. Indirect aggression correlates negatively with a disappointment -0.324 for p <0.05. Important differences were shown in the second stage of the examination among groups examined on the scale inspection of the aggressive behaviour. Substantial results weren't demonstrated on scales: emotional self-aggression, hostility towards the environment and directed outside aggression In the regression analysis we received a statistically significant result: controlling an aggressive behavior correlates negatively with disappointment -0, 355 p <0,01. However, no statistically significant results were received from the partners of obese people. Weight loss after gastric-by-pass surgery has the significant impact on the rarer occurrence of an aggressive behavior, which improving the quality of the connubial or cohabitation relationship.

Blastic transformation in chronic myelogenous leukemia: experience with 50 patients.

PubMed

Marks, S M; McCaffrey, R; Rosenthal, D S; Moloney, W C

1978-01-01

Fifty consecutive patients with blastic chronic myelogenous leukemia were evaluated clinically, morphologically, biochemically, and therapeutically. Forty-five patients had a preceding stable phase (38 Ph'+, 7 Ph'-); five patients presented with de novo Ph+ blast crisis. The most frequent clinical signs of impending blast crisis were weakness, fatigue, increasing splenomegaly, anemia, thrombocytopenia, marrow fibrosis, and a rising neutrophil alkaline phosphatase. Fever (unrelated to infection), skin infiltration, lymphadenopathy, hepatomegaly, thrombocytosis, and basophilia were much less common. The development of aneuploidy occurred in less than one-half of the total group. Myeloblastic morphology at blastic transformation was most frequent with occasional lymphoblastic, promyelocytic, and undifferentiated cases seen. Terminal deoxynucleotidyl transferase was present in one-third of the patients, but had no clear-cut relationship to the morphology. Response to treatment was generally disappointing (two complete and 15 partial remissions in 45 treated patients).
Inside Success: Strategies of 25 Effective Small High Schools in NYC. Executive Summary

ERIC Educational Resources Information Center

Villavicencio, Adriana; Marinell, William H.

2014-01-01

For decades, New York City's high school graduation rates hovered at or below 50 percent. In attempt to turn around these disappointing results, the NYC Department of Education enacted a series of large-scale reforms, including opening hundreds of new "small schools of choice" (SSCs). Recent research by MDRC has shown that these schools…
Inside Success: Strategies of 25 Effective Small High Schools in NYC. Technical Appendices

ERIC Educational Resources Information Center

Villavicencio, Adriana; Marinell, William H.

2014-01-01

For decades, New York City's high school graduation rates hovered at or below 50 percent. In attempt to turn around these disappointing results, the NYC Department of Education enacted a series of large-scale reforms, including opening hundreds of new "small schools of choice" (SSCs). Recent research by MDRC has shown that these schools…
Inside Success: Strategies of 25 Effective Small High Schools in NYC. Report

ERIC Educational Resources Information Center

Villavicencio, Adriana; Marinell, William H.

2014-01-01

For decades, New York City's high school graduation rates hovered at or below 50 percent. In attempt to turn around these disappointing results, the NYC Department of Education enacted a series of large-scale reforms, including opening hundreds of new "small schools of choice" (SSCs). Recent research by MDRC has shown that these schools…
The New Regionalism in Sub-Saharan Africa: More Than Meets the Eye? Policy Brief No. 20

ERIC Educational Resources Information Center

Goldstein, Andrea

2002-01-01

Following independence in sub-Saharan Africa in the 1960s, traditional integration strategies produced disappointing results in most instances, as they started with very modest levels of intra-regional trade, marked differences in income and industrialisation levels and diffuse fiscal weakness. They also had a strong protectionist bias, trying to…
Living in interesting times: applying creative strategic planning.

PubMed

Jessome, P

1995-01-01

Rapidly changing expectations and environments have put health care facilities under increasing pressure. Using traditional strategic planning to deal with these challenges has often produced disappointing results. This article outlines a different approach, based on Robert Fritz's model of the creative process, and discusses its application in Kiwanis Lodge in West Vancouver, an intermediate care facility.
Professional Careers for Women--An Opportunity for All. Information Bank Working Paper Number 2716.

ERIC Educational Resources Information Center

Allerton, Anne

Twenty-one women who were full- or part-time returning students of higher education in England, most at the Dorset Institute, were interviewed about their secondary schooling, age of leaving school, reason for disappointing examination results, career guidance given at school, parental influence, career aspirations, first job after leaving school,…
Problem-Based Learning, Scaffolding, and Coaching: Improving Student Outcomes through Structured Group Time

ERIC Educational Resources Information Center

Murray, Lynn M.

2012-01-01

Live-client projects are increasingly used in marketing coursework. However, students, instructors, and clients are often disappointed by the results. This paper reports an approach drawn from the problem-based learning, scaffolding, and team formation and coaching literatures that uses favor of a series of workshops designed to guide students in…
Turning a Molehill into a Mountain? How Reading Curricula Are Failing the Poor Worldwide

ERIC Educational Resources Information Center

Abadzi, Helen

2016-01-01

Reading programs for low-income populations often give disappointing results. Failures may be partly due to a neglect of practice in decoding letters. Visual stimuli are best learned symbol by symbol, with pattern analogies and much practice to unite smaller components and speed up identification. The prerequisite for comprehending volumes of text…
The U.S. Writing Center Model for High Schools Goes to Germany: And What Is Coming Back?

ERIC Educational Resources Information Center

Braer, Gerd

2006-01-01

The 2000 and 2003 international studies of the Program for International Student Assessment (PISA) among all Organization for Economic Cooperation and Development (OECD) countries presented disappointing results for Germany's fifteen-year-old students' reading skills. These studies pointed out two necessities for future reform: to extend the…
Industrial Democracy: Conflict or Cooperation? Series on Public Issues No. 12.

ERIC Educational Resources Information Center

Pejovich, Steve

In this booklet, one of a series intended to apply economic principles to major social and political issues of the day, it is argued that government regulation of business has produced disappointing results, as evidenced by the steady rise of inflation rates in the 1970's, continuing unemployment, declining labor productivity, and increases in…
[Central aleolar choroidal dystrophy in sibilings coexisting with alopecia].

PubMed

Brydak-Godowska, Joanna; Dróbecka-Brydak, Ewa; Paćkowska, Maria; Kecik, Dariusz

2007-01-01

Central areolar choroidal dystrophy is localized in macular region and is characterized by atrophy of pigment epithelium, photoreceptors and choriocapillaris. This paper presents the history of two sibilings at the age of 23 and 30, with central aleolar choroidal dystrophy coexisting with alopecia. The results of erg, eog and fluorescein angiography are presented. The results of therapy for glaucoma associated with the Sturge-Weber syndrome are often disappointing.
Put on a happy face! Inhibitory control and socioemotional knowledge predict emotion regulation in 5- to 7-year-olds.

PubMed

Hudson, Amanda; Jacques, Sophie

2014-07-01

Children's developing capacity to regulate emotions may depend on individual characteristics and other abilities, including age, sex, inhibitory control, theory of mind, and emotion and display rule knowledge. In the current study, we examined the relations between these variables and children's (N=107) regulation of emotion in a disappointing gift paradigm as well as their relations with the amount of effort to control emotion children exhibited after receiving the disappointing gift. Regression analyses were also conducted to identify unique predictors. Children's understanding of others' emotions and emotion display rules, as well as their inhibitory control skills, emerged as significant correlates of emotion regulation and predicted children's responses to the disappointing gift even after controlling for other relevant variables. Age and inhibitory control significantly predicted the amount of overt effort that went into regulating emotions, as did emotion knowledge (albeit only marginally). Together, findings suggest that effectively regulating emotions requires (a) knowledge of context-appropriate emotions along with (b) inhibitory skills to implement that knowledge. Copyright © 2014 Elsevier Inc. All rights reserved.
Clinical role of non-invasive assessment of portal hypertension.

PubMed

Bolognesi, Massimo; Di Pascoli, Marco; Sacerdoti, David

2017-01-07

Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis ( i.e ., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field.
Clinical role of non-invasive assessment of portal hypertension

PubMed Central

Bolognesi, Massimo; Di Pascoli, Marco; Sacerdoti, David

2017-01-01

Measurement of portal pressure is pivotal in the evaluation of patients with liver cirrhosis. The measurement of the hepatic venous pressure gradient represents the reference method by which portal pressure is estimated. However, it is an invasive procedure that requires significant hospital resources, including experienced staff, and is associated with considerable cost. Non-invasive methods that can be reliably used to estimate the presence and the degree of portal hypertension are urgently needed in clinical practice. Biochemical and morphological parameters have been proposed for this purpose, but have shown disappointing results overall. Splanchnic Doppler ultrasonography and the analysis of microbubble contrast agent kinetics with contrast-enhanced ultrasonography have shown better accuracy for the evaluation of patients with portal hypertension. A key advancement in the non-invasive evaluation of portal hypertension has been the introduction in clinical practice of methods able to measure stiffness in the liver, as well as stiffness/congestion in the spleen. According to the data published to date, it appears to be possible to rule out clinically significant portal hypertension in patients with cirrhosis (i.e., hepatic venous pressure gradient ≥ 10 mmHg) with a level of clinically-acceptable accuracy by combining measurements of liver stiffness and spleen stiffness along with Doppler ultrasound evaluation. It is probable that the combination of these methods may also allow for the identification of patients with the most serious degree of portal hypertension, and ongoing research is helping to ensure progress in this field. PMID:28104976
Disappointment Reach, Australia as seen from STS-67 Endeavour

NASA Technical Reports Server (NTRS)

1995-01-01

A nearly vertical view of Disappointment Reach and surroundings. Ripple-like patterns extending at right angles to the tidal flow can be discerned on shoals. Relict sand dune patterns, crests unvegetated, are evident on the western side of the estuary. Red mud brought down the Mooramel River on the east side of the estuary does extend into the shallow water of the inter-tidal lagoons. Most of the light-colored water along the coast, represents shoals of lime sediment. Patterns of sediment distribution by tides, waves, streams, and wind combine to create a complex and colorful scene.
Disappointment Reach, Australia as seen from STS-67 Endeavour

NASA Image and Video Library

1995-03-14

A nearly vertical view of Disappointment Reach and surroundings. Ripple-like patterns extending at right angles to the tidal flow can be discerned on shoals. Relict sand dune patterns, crests unvegetated, are evident on the western side of the estuary. Red mud brought down the Mooramel River on the east side of the estuary does extend into the shallow water of the inter-tidal lagoons. Most of the light-colored water along the coast, represents shoals of lime sediment. Patterns of sediment distribution by tides, waves, streams, and wind combine to create a complex and colorful scene.
Social Impacts of McClellan-Kerr Navigation System: A Study of Public Sector Response to Water Resource Development,

DTIC Science & Technology

1981-12-01

results are disappointing as tonnage for 1976 is the lowest of the five ports. Muskogee has not produced results commensurate with investment, both...the waterway. At the time of writing, no plants that need to use the waterway have been built at the industrial site. This situation results in part...c.b.d. originally was located near the river, growth results in decreasing accessibility for residents of the urban area. Efforts are underway in each
Molecular oncogenesis of chondrosarcoma: impact for targeted treatment.

PubMed

Speetjens, Frank M; de Jong, Yvonne; Gelderblom, Hans; Bovée, Judith V M G

2016-07-01

The prognosis of patients with unresectable or metastatic chondrosarcoma of the bone is poor. Chondrosarcomas are in general resistant to chemotherapy and radiotherapy. This review discusses recent developments in the characterization of molecular pathways involved in the oncogenesis of chondrosarcoma that should be explored to improve prognosis of patients with advanced chondrosarcoma. The different oncogenic pathways for chondrosarcoma have become better defined. These include alterations in pathways such as isocitrate dehydrogenase mutation, hedgehog signalling, the retinoblastoma protein and p53 pathways, apoptosis and survival mechanisms, and several tyrosine kinases. These specific alterations can be employed for use in clinical interventions in advanced chondrosarcoma. As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.
Targeting key proximal drivers of type 2 inflammation in disease.

PubMed

Gandhi, Namita A; Bennett, Brandy L; Graham, Neil M H; Pirozzi, Gianluca; Stahl, Neil; Yancopoulos, George D

2016-01-01

Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines - interleukin-4 (IL-4), IL-5 and IL-13 - represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL-4, IL-5 or IL-13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an 'allergic' phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL-4 and IL-13 has shown significant clinical activity in diseases that are often co-morbid with asthma - atopic dermatitis and chronic sinusitis with nasal polyps - supporting the hypothesis that targeting a central 'driver pathway' could benefit multiple allergic diseases.

Chagas disease drug discovery: toward a new era.

PubMed

Chatelain, Eric

2015-01-01

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed. © 2014 Society for Laboratory Automation and Screening.
Helminths and immunological tolerance.

PubMed

Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

2014-01-27

Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world's population. It is now well established that the parasites' success is the result of active immunomodulation of their hosts' immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice.
Why Targeted Therapies are Necessary for Systemic Lupus Erythematosus

PubMed Central

Durcan, Laura; Petri, Michelle

2016-01-01

Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side-effects. Current management strategies rely heavily on non-specific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic pre-clinical data and promising early phase studies have ultimately been disappointing in phase III randomized controlled studies. Recent efforts have focused on B cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated including interferon alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID:27497251
Malignant pleural mesothelioma: a phase II trial with docetaxel.

PubMed

Vorobiof, D A; Rapoport, B L; Chasen, M R; Abratt, R P; Cronje, N; Fourie, L; McMichael, G; Hacking, D

2002-03-01

Current cytotoxic therapy has been of limited benefit to patients with malignant pleural mesothelioma. Single agent chemotherapy has been extensively evaluated in small series of phase II clinical trials, with disappointing responses. Docetaxel, an effective taxane in the treatment of advanced breast cancer and non-small-cell lung cancer, was administered intravenously at a dose of 100 mg/m2 every 3 weeks to 30 chemotherapy naive patients with malignant pleural mesothelioma in a prospective multi-institutional phase II clinical trial. An objective response rate (partial responses) of 10% was documented. Additionally, 21% of the patients had minor responses (intention-to-treat analysis). Three patients died within 2 weeks post-first cycle of therapy, although only one patient's death was directly attributed to the investigational drug, whilst in the majority of the patients, manageable and treatable toxicities were encountered. In this phase II clinical trial, docetaxel proved to be mildly effective in the treatment of patients with malignant pleural mesothelioma.
Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling.

PubMed

Kirkpatrick, D Lynn; Powis, Garth

2017-02-20

There are a number of redox-active anticancer agents currently in development based on the premise that altered redox homeostasis is necessary for cancer cell's survival. Recent Advances: This review focuses on the relatively few agents that target cellular redox homeostasis to have entered clinical trial as anticancer drugs. The success rate of redox anticancer drugs has been disappointing compared to other classes of anticancer agents. This is due, in part, to our incomplete understanding of the functions of the redox targets in normal and cancer tissues, leading to off-target toxicities and low therapeutic indexes of the drugs. The field also lags behind in the use biomarkers and other means to select patients who are most likely to respond to redox-targeted therapy. If we wish to derive clinical benefit from agents that attack redox targets, then the future will require a more sophisticated understanding of the role of redox targets in cancer and the increased application of personalized medicine principles for their use. Antioxid. Redox Signal. 26, 262-273.
New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes

PubMed Central

Senni, Michele; Paulus, Walter J.; Gavazzi, Antonello; Fraser, Alan G.; Díez, Javier; Solomon, Scott D.; Smiseth, Otto A.; Guazzi, Marco; Lam, Carolyn S. P.; Maggioni, Aldo P.; Tschöpe, Carsten; Metra, Marco; Hummel, Scott L.; Edelmann, Frank; Ambrosio, Giuseppe; Stewart Coats, Andrew J.; Filippatos, Gerasimos S.; Gheorghiade, Mihai; Anker, Stefan D.; Levy, Daniel; Pfeffer, Marc A.; Stough, Wendy Gattis; Pieske, Burkert M.

2014-01-01

The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little or no progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despite the high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist. There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without true heart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patients with HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research should be applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and it examines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected in clinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed. PMID:25104786
Molecular genetics research in ADHD: ethical considerations concerning patients' benefit and resource allocation.

PubMed

Rothenberger, Lillian Geza

2012-12-01

Immense resource allocations have led to great data output in genetic research. Concerning ADHD resources spent on genetic research are less than those spent on clinical research. But there are successful efforts made to increase support for molecular genetics research in ADHD. Concerning genetics no evidence based conclusive results have significant impact on prevention, diagnosis or treatment yet. With regard to ethical aspects like the patients' benefit and limited resources the question arises if it is indicated to think about a new balance of resource allocation between molecular genetics and non-genetics research in ADHD. An ethical reflection was performed focusing on recent genetic studies and reviews based on a selective literature search. There are plausible reasons why genetic research results in ADHD are somehow disappointing for clinical practice so far. Researchers try to overcome these gaps systematically, without knowing what the potential future benefits for the patients might be. Non-genetic diagnostic/therapeutic research may lead to clinically relevant findings within a shorter period of time. On the other hand, non-genetic research in ADHD may be nurtured by genetic approaches. But, with the latter there exist significant risks of harm like stigmatization and concerns regarding data protection. Isolated speeding up resources of genetic research in ADHD seems questionable from an ethical point of view. There is a need to find a new balance of resource allocation between genetic and non-genetic research in ADHD, probably by integrating genetics more systematically into clinical research. A transdisciplinary debate is recommended. Copyright © 2012 Wiley Periodicals, Inc.
Teachers' Nature of Science Implementation Practices 2-5 Years after Having Completed an Intensive Science Education Program

ERIC Educational Resources Information Center

Herman, Benjamin C.; Clough, Michael P.; Olson, Joanne K.

2013-01-01

Few, if any, studies have examined the impact of nature of science (NOS) instruction on science teachers' practices 2 or more years after completing a science teacher education program. Extant studies on preservice and first-year teachers' NOS teaching practices have had disappointing results, with few teachers valuing NOS as a cognitive objective…
The Paper Implementation of the German Educational Standards in Geography for the Intermediate School Certificate in the German Federal States

ERIC Educational Resources Information Center

Schöps, Andreas

2017-01-01

Up to the publication of the results of Germany's first participation in the PISA study in 2001, there had been no national educational standards in Germany's 16 federal states. In the aftermath of the discussions about the disappointing outcomes, Germany's federal states decided to develop national standards, yet focusing on "core…
Implementing a sustainable clinical supervision model for Isles nurses in Orkney.

PubMed

Hall, Ian

2018-03-02

The Isles Network of Care (INOC) community nurses work at the extreme of the remote and rural continuum, working mostly as lone practitioners. Following the development of sustainable clinical supervision model for Isles nurses in Orkney, clinical supervision was found to improve both peer support and governance for this group of isolated staff. A literature overview identified the transition of clinical supervision in general nursing over 24 years from 'carrot' to 'stick'. The study included a questionnaire survey that was sent to the 2017 Queen's Nursing Institute Scotland cohort to elicit information about the nurses' experience of clinical supervision. The survey found that 55% provide supervision and 40% receive it. Health board encouragement of its use was found to be disappointingly low at 40%. The INOC nurses were surveyed about the new peer-support (restorative) model, which relies on video-conference contact to allow face to face interaction between isolated isles nurses. Feedback prompted a review of clinical supervision pairings, and the frequency and methods of meeting. The need for supervisor training led to agreement with the Remote and Rural Health Education Alliance to provide relevant support. The perceived benefits of supervision included increased support and reflection, and improved relationships with isolated colleagues.
Predicting pneumococcal community-acquired pneumonia in the emergency department: evaluation of clinical parameters.

PubMed

Huijts, S M; Boersma, W G; Grobbee, D E; Gruber, W C; Jansen, K U; Kluytmans, J A J W; Kuipers, B A F; Palmen, F; Pride, M W; Webber, C; Bonten, M J M

2014-12-01

The aim of this study was to quantify the value of clinical predictors available in the emergency department (ED) in predicting Streptococcus pneumoniae as the cause of community-acquired pneumonia (CAP). A prospective, observational, cohort study of patients with CAP presenting in the ED was performed. Pneumococcal aetiology of CAP was based on either bacteraemia, or S. pneumoniae being cultured from sputum, or urinary immunochromatographic assay positivity, or positivity of a novel serotype-specific urinary antigen detection test. Multivariate logistic regression was used to identify independent predictors and various cut-off values of probability scores were used to evaluate the usefulness of the model. Three hundred and twenty-eight (31.0%) of 1057 patients with CAP had pneumococcal CAP. Nine independent predictors for pneumococcal pneumonia were identified, but the clinical utility of this prediction model was disappointing, because of low positive predictive values or a small yield. Clinical criteria have insufficient diagnostic capacity to predict pneumococcal CAP. Rapid antigen detection tests are needed to diagnose S. pneumoniae at the time of hospital admission. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.
Deanol and physostigmine in the treatment of L-dopa-induced dyskinesias.

PubMed

Lindeboom, S F; Lakke, J P

1978-08-01

Deanol and placebo were administered to 10 parkinsonian patients with levodopa-induced dyskinesias in a double-blind, crossover fashion. Deanol and placebo did not differ significantly in their effects on dyskinesias. The reported properties of deanol seem to be attributable to a placebo effect. There was no correlation with the results of the physostigmine test. Despite these disappointing results deanol remains intriguing, because in individual cases remarkable improvements on dyskinesias are reported.
Predicting HIV RNA virologic outcome at 52-weeks follow-up in antiretroviral clinical trials. The INCAS and AVANTI Study Groups.

PubMed

Raboud, J M; Rae, S; Montaner, J S

2000-08-15

To determine the ability of intermediate plasma viral load (pVL) measurements to predict virologic outcome at 52 weeks of follow-up in clinical trials of antiretroviral therapy. Individual patient data from three clinical trials (INCAS, AVANTI-2 and AVANTI-3) were combined into a single database. Virologic success was defined to be plasma viral load (pVL) <500 copies/ml at week 52. The sensitivity and specificity of intermediate pVL measurements below the limit of detection, 100, 500, 1000, and 5000 copies/ml to predict virologic success were calculated. The sensitivity, specificity, and positive and negative predictive values of a pVL measurement <1000 copies/ml at week 16 to predict virologic outcome at week 52 were 74%, 74%, 48%, and 90%, respectively, for patients on double therapy. For patients on triple therapy, the sensitivity, specificity, and positive and negative predictive values of a pVL measurement <50 copies/ml at week 16 to predict virologic outcome were 68%, 68%, 80%, and 47%, respectively. For patients receiving double therapy, a poor virologic result at an intermediate week of follow-up is a strong indicator of virologic failure at 52 weeks whereas intermediate virologic success is no guarantee of success at 1 year. For patients on triple therapy, disappointing intermediate results do not preclude virologic success at 1 year and intermediate successes are more likely to be sustained.
Predictors of children's prosocial lie-telling: Motivation, socialization variables, and moral understanding.

PubMed

Popliger, Mina; Talwar, Victoria; Crossman, Angela

2011-11-01

Children tell prosocial lies for self- and other-oriented reasons. However, it is unclear how motivational and socialization factors affect their lying. Furthermore, it is unclear whether children's moral understanding and evaluations of prosocial lie scenarios (including perceptions of vignette characters' feelings) predict their actual prosocial behaviors. These were explored in two studies. In Study 1, 72 children (36 second graders and 36 fourth graders) participated in a disappointing gift paradigm in either a high-cost condition (lost a good gift for a disappointing one) or a low-cost condition (received a disappointing gift). More children lied in the low-cost condition (94%) than in the high-cost condition (72%), with no age difference. In Study 2, 117 children (42 preschoolers, 41 early elementary school age, and 34 late elementary school age) participated in either a high- or low-cost disappointing gift paradigm and responded to prosocial vignette scenarios. Parents reported on their parenting practices and family emotional expressivity. Again, more children lied in the low-cost condition (68%) than in the high-cost condition (40%); however, there was an age effect among children in the high-cost condition. Preschoolers were less likely than older children to lie when there was a high personal cost. In addition, compared with truth-tellers, prosocial liars had parents who were more authoritative but expressed less positive emotion within the family. Finally, there was an interaction between children's prosocial lie-telling behavior and their evaluations of the protagonist's and recipient's feelings. Findings contribute to understanding the trajectory of children's prosocial lie-telling, their reasons for telling such lies, and their knowledge about interpersonal communication. Copyright © 2011 Elsevier Inc. All rights reserved.
Fairness decisions in response to emotions: a functional MRI study among criminal justice-involved boys with conduct disorder

PubMed Central

Lelieveld, Gert-Jan; Aghajani, Moji; Boon, Albert E.; van der Wee, Nic J. A.; Popma, Arne; Vermeiren, Robert R. J. M.; Colins, Olivier F.

2016-01-01

Research suggests that individuals with conduct disorder (CD) are marked by social impairments, such as difficulties in processing the affective reactions of others. Little is known, though, about how they make decisions during social interactions in response to emotional expressions of others. In this study, we therefore investigated the neural mechanisms underlying fairness decisions in response to communicated emotions of others in aggressive, criminal justice-involved boys with CD (N = 32) compared with typically developing (TD) boys (N = 33), aged 15–19 years. Participants received written emotional responses (angry, disappointed or happy) from peers in response to a previous offer and then had to make fairness decisions in a version of the Dictator Game. Behavioral results showed that CD boys did not make differential fairness decisions in response to the emotions, whereas the TD boys did show a differentiation and also responded more unfair to happy reactions than the CD boys. Neuroimaging results revealed that when receiving happy vs disappointed and angry reactions, the CD boys showed less activation than the TD boys in the temporoparietal junction and supramarginal gyrus, regions involved in perspective taking and attention. These results suggest that boys with CD have difficulties with processing explicit emotional cues from others on behavioral and neural levels. PMID:26926604
Death receptors as targets in cancer.

PubMed

Micheau, O; Shirley, S; Dufour, F

2013-08-01

Anti-tumour therapies based on the use pro-apoptotic receptor agonists, including TNF-related apoptosis-inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL-R1 or TRAIL-R2, have been disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti-cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials. This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8. © 2013 The British Pharmacological Society.
Discontinued drugs in 2012: cardiovascular drugs.

PubMed

Zhao, Hong-Ping; Jiang, Hong-Min; Xiang, Bing-Ren

2013-11-01

The continued high rate of cardiovascular morbidity and mortality has attracted wide concern and great attention of pharmaceutical industry. In order to reduce the attrition of cardiovascular drug R&D, it might be helpful recapitulating previous failures and identifying the potential factors to success. This perspective mainly analyses the 30 cardiovascular drugs dropped from clinical development in 2012. Reasons causing the termination of the cardiovascular drugs in the past 5 years are also tabulated and analysed. The analysis shows that the attrition is highest in Phase II trials and financial and strategic factors and lack of clinical efficacy are the principal reasons for these disappointments. To solve the four problems (The 'better than the Beatles' problem, the 'cautious regulator' problem, the 'throw money at it' tendency and the 'basic researchbrute force' bias) is recommended as the main measure to increase the number and quality of approvable products.
“Putting It All Together” to Improve Resuscitation Quality

PubMed Central

Sutton, Robert M.; Nadkarni, Vinay; Abella, Benjamin S.

2013-01-01

Cardiac arrest is a major public health problem affecting thousands of individuals each year in both the before hospital and in-hospital settings. However, although the scope of the problem is large, the quality of care provided during resuscitation attempts frequently does not meet quality of care standards, despite evidence-based cardiopulmonary resuscitation (CPR) guidelines, extensive provider training, and provider credentialing in resuscitation medicine. Although this fact may be disappointing, it should not be surprising. Resuscitation of the cardiac arrest victim is a highly complex task requiring coordination between various levels and disciplines of care providers during a stressful and relatively infrequent clinical situation. Moreover, it requires a targeted, high-quality response to improve clinical outcomes of patients. Therefore, solutions to improve care provided during resuscitation attempts must be multifaceted and targeted to the diverse number of care providers to be successful. PMID:22107978
Three-dimensional bio-printing: A new frontier in oncology research

PubMed Central

Charbe, Nitin; McCarron, Paul A; Tambuwala, Murtaza M

2017-01-01

Current research in oncology deploys methods that rely principally on two-dimensional (2D) mono-cell cultures and animal models. Although these methodologies have led to significant advancement in the development of novel experimental therapeutic agents with promising anticancer activity in the laboratory, clinicians still struggle to manage cancer in the clinical setting. The disappointing translational success is attributable mainly to poor representation and recreation of the cancer microenvironment present in human neoplasia. Three-dimensional (3D) bio-printed models could help to simulate this micro-environment, with recent bio-printing of live human cells demonstrating that effective in vitro replication is achievable. This literature review outlines up-to-date advancements and developments in the use of 3D bio-printed models currently being used in oncology research. These innovative advancements in 3D bio-printing open up a new frontier for oncology research and could herald an era of progressive clinical cancer therapeutics. PMID:28246583
Advances in Therapeutic Cancer Vaccines.

PubMed

Wong, Karrie K; Li, WeiWei Aileen; Mooney, David J; Dranoff, Glenn

2016-01-01

Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines. © 2016 Elsevier Inc. All rights reserved.

The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions.

PubMed

Cohen, Michael V; Downey, James M

2017-09-26

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y 12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y 12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.
Acceptance and barriers pertaining to a general practice decision support system for multiple clinical conditions: A mixed methods evaluation.

PubMed

Arts, Derk L; Medlock, Stephanie K; van Weert, Henk C P M; Wyatt, Jeremy C; Abu-Hanna, Ameen

2018-01-01

Many studies have investigated the use of clinical decision support systems as a means to improve care, but have thus far failed to show significant effects on patient-related outcomes. We developed a clinical decision support system that attempted to address issues that were identified in these studies. The system was implemented in Dutch general practice and was designed to be both unobtrusive and to respond in real time. Despite our efforts, usage of the system was low. In the current study we perform a mixed methods evaluation to identify remediable barriers which led to disappointing usage rates for our system. A mixed methods evaluation employing an online questionnaire and focus group. The focus group was organized to clarify free text comments and receive more detailed feedback from general practitioners. Topics consisted of items based on results from the survey and additional open questions. The response rate for the questionnaire was 94%. Results from the questionnaire and focus group can be summarized as follows: The system was perceived as interruptive, despite its design. Participants felt that there were too many recommendations and that the relevance of the recommendations varied. Demographic based recommendations (e.g. age) were often irrelevant, while specific risk-based recommendations (e.g. diagnosis) were more relevant. The other main barrier to use was lack of time during the patient visit. These results are likely to be useful to other researchers who are attempting to address the problems of interruption and alert fatigue in decision support.
Antioxidants and Coronary Artery Disease: From Pathophysiology to Preventive Therapy

PubMed Central

Leopold, Jane A.

2014-01-01

Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials of selected antioxidants as primary and secondary prevention to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidant as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials. This review will focus on the contemporary evidence that is the basis for our current understanding of the role of antioxidants in cardiovascular disease prevention. PMID:25369999
[Extensive cutaneous chromomycosis: Efficacy of combined terbinafine and cryotherapy].

PubMed

Elkhachine, Y; Elbenaye, J; Er-Rami, M; Sakkah, A; Jakar, A; Elhaouri, M

2018-05-17

Chromomycosis is a chronic fungal skin infection, mainly affecting the limbs. It is responsible for severe morbidity and its treatment remains long and disappointing. Rarely described in Morocco, we report a new observation that has evolved very well under treatment combining terbinafine and cryotherapy over a short duration. A 56-year-old patient, immunocompetent, had a pustular and crusty placard on both forearms that had evolved for a year. Mycological examination showed fumagoid bodies and cutaneous biopsy showed epithelioid granulomas and giant cells without necrosis. The PCR confirmed a chromomycosis at Fonsecaea pedrosoi. HIV serology was negative. Treatment with terbinafine 250mg/d for 6months combined to cryotherapy resulted in complete remission with initial clinical improvement after only 3 weeks. Chromomycosis occurs increasingly in non-tropical areas. If diagnostic methods become more effective, management remains difficult and poorly codified. Terbinafine-cryotherapy combination would bring a lot of benefits with a little risk to bothpractitioner and patient. This combined treatment would constitute an excellent therapeutic alternative because of its efficiency, feasibility, low cost, method of administration and aesthetic result. Copyright © 2018 Elsevier Masson SAS. All rights reserved.
Group 2 Pulmonary Hypertension: Pulmonary Venous Hypertension: Epidemiology and Pathophysiology.

PubMed

Clark, Craig B; Horn, Evelyn M

2016-08-01

Pulmonary hypertension from left heart disease (PH-LHD) is the most common form of PH, defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≥15 mm Hg. PH-LHD development is associated with more severe left-sided disease and its presence portends a poor prognosis, particularly once right ventricular failure develops. Treatment remains focused on the underlying LHD and despite initial enthusiasm for PH-specific therapies, most studies have been disappointing and their routine clinical use cannot be recommended. More work is urgently needed to better understand the pathophysiology underlying this disease and to develop effective therapeutic strategies. Copyright © 2016 Elsevier Inc. All rights reserved.
Tissue engineering of the bladder--reality or myth? A systematic review.

PubMed

Sloff, Marije; Simaioforidis, Vasileios; de Vries, Rob; Oosterwijk, Egbert; Feitz, Wout

2014-10-01

We systematically reviewed preclinical studies in the literature to evaluate the potential of tissue engineering of the bladder. Study outcomes were compared to the available clinical evidence to assess the feasibility of tissue engineering for future clinical use. Preclinical studies of tissue engineering for bladder augmentation were identified through a systematic search of PubMed and Embase™ from January 1, 1980 to January 1, 2014. Primary studies in English were included if bladder reconstruction after partial cystectomy was performed using a tissue engineered biomaterial in any animal species, with cystometric bladder capacity as an outcome measure. Outcomes were compared to clinical studies available at http://www.clinicaltrials.gov and published clinical studies. A total of 28 preclinical studies are included, demonstrating remarkable heterogeneity in study characteristics and design. Studies in which preoperative bladder volumes were compared to postoperative volumes were considered the most clinically relevant (18 studies). Bladder augmentation through tissue engineering resulted in a normal bladder volume in healthy animals, with the influence of a cellular component being negligible. Furthermore, experiments in large animal models (pigs and dogs) approximated the desired bladder volume more accurately than in smaller species. The initial clinical experience was based on seemingly predictive healthy animal models with a promising outcome. Unfortunately these results were not substantiated in all clinical trials, revealing dissimilar outcomes in different clinical/disease backgrounds. Thus, the translational predictability of a model using healthy animals might be questioned. Through this systematic approach we present an unbiased overview of all published preclinical studies investigating the effect of bladder tissue engineering on cystometric bladder capacity. Preclinical research in healthy animals appears to show the feasibility of bladder augmentation by tissue engineering. However, in view of the disappointing clinical results based on healthy animal models new approaches should also be evaluated in preclinical models using dysfunctional/diseased bladders. This endeavor may aid in the development of clinically applicable tissue engineered bladder augmentation with satisfactory long-term outcome. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
[Disease Experience after Many Years of Orthopedic Therapy in Childhood].

PubMed

Schwarze, Martin; Gerigk, Carina; Schulmeister, Martin; Schiltenwolf, Marcus

2018-06-22

The orthopedic medical history of the now 56-year-old Mr. Z began immediately after his birth with an inpatient clubfoot therapy. With the onset of adolescence, multilocular pain began. The long-standing patient career was characterized by disappointment about the early onset and recurrent need for treatment. The disappointment motive is closely related to the relationship between the patient and his mother. The biography illustrates the intertwining of early (orthopedic) treatment, primary bonding and disease experiences. A multimodal pain therapy was able to target Mr. Z, create positive body experiences and finally reduce the pain. © Georg Thieme Verlag KG Stuttgart · New York.
Mid-infrared coronary laser angioplasty with multifiber catheters

NASA Astrophysics Data System (ADS)

White, Christopher J.; Ramee, Stephen R.; Collins, Tyrone J.

1993-06-01

Mid-infrared laser wavelengths offer advantages as a source for coronary angioplasty based upon the excellent fiberoptic transmission and the enhanced tissue absorption of these photons. We report the results of a pilot clinical trial of a Holmium:YAG (2.1 micrometers ) coronary laser angioplasty using a prototype (1.6 mm and 2.0 mm) multifiber catheters. Coronary laser angioplasty with or without adjunctive balloon angioplasty or directional atherectomy was performed in 14 patients with 17 coronary stenoses. Laser success was obtained in 13/14 (93%) patients and 16/17 (94%) lesions. Uncomplicated procedural success was achieved in 9/14 (64%) patients and 12/17 (71%) lesions. Our initial laser success rate was very encouraging using this prototype multifiber catheter with a holmium:YAG laser. However, our overall procedural success rate was disappointing, and not superior to that expected with conventional angioplasty alone. The holmium laser remains an attractive energy source for laser angioplasty, but its utility is limited by catheters which create inadequate channels for stand-alone laser angioplasty.
Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis

PubMed Central

Dorst, Johannes; Ludolph, Albert C.; Huebers, Annemarie

2017-01-01

In this review, we summarize the most important recent developments in the treatment of amyotrophic lateral sclerosis (ALS). In terms of disease-modifying treatment options, several drugs such as dexpramipexole, pioglitazone, lithium, and many others have been tested in large multicenter trials, albeit with disappointing results. Therefore, riluzole remains the only directly disease-modifying drug. In addition, we discuss antisense oligonucleotides (ASOs) as a new and potentially causal treatment option. Progress in symptomatic treatments has been more important. Nutrition and ventilation are now an important focus of ALS therapy. Several studies have firmly established that noninvasive ventilation improves patients’ quality of life and prolongs survival. On the other hand, there is still no consensus regarding best nutritional management, but big multicenter trials addressing this issue are currently ongoing. Evidence regarding secondary symptoms like spasticity, muscle cramps or sialorrhea remains generally scarce, but some new insights will also be discussed. Growing evidence suggests that multidisciplinary care in specialized clinics improves survival. PMID:29399045
HIV-1 vaccines

PubMed Central

Excler, Jean-Louis; Robb, Merlin L; Kim, Jerome H

2014-01-01

The development of a safe and effective preventive HIV-1 vaccine remains a public health priority. Despite scientific difficulties and disappointing results, HIV-1 vaccine clinical development has, for the first time, established proof-of-concept efficacy against HIV-1 acquisition and identified vaccine-associated immune correlates of risk. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop correlated with decreased risk of HIV infection, while Env-specific IgA directly correlated with increased risk. The development of vaccine strategies such as improved envelope proteins formulated with potent adjuvants and DNA and vectors expressing mosaics, or conserved sequences, capable of eliciting greater breadth and depth of potentially relevant immune responses including neutralizing and non-neutralizing antibodies, CD4+ and CD8+ cell-mediated immune responses, mucosal immune responses, and immunological memory, is now proceeding quickly. Additional human efficacy trials combined with other prevention modalities along with sustained funding and international collaboration remain key to bring an HIV-1 vaccine to licensure. PMID:24637946
The Impact of the PARSEL Way to Teach Science in Germany on Interest, Scientific Literacy, and German National Standards

ERIC Educational Resources Information Center

Graeber, Wolfgang; Lindner, Martin

2008-01-01

This paper shows how PARSEL modules help to realize the German standards in practice. After analyzing the disappointing results of the TIMSS- and PISA-studies, which caused a kind of "PISA-shock" in Germany, and looking at school systems of winning nations, several changes have been initiated in the German educational system. The most…
Sharpening Our Plowshares: Applying the Lessons of Counterinsurgency to Development and Humanitarian Aid

DTIC Science & Technology

2013-01-01

ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION /AVAILABILITY STATEMENT Approved for public...release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT...the US Agency for International Development [USAID] or the military) have distributed the aid, the results have been disappointing.10 Individual
Public Television Channels in New York City: The First Six Months.

ERIC Educational Resources Information Center

Calhoun, Richard

The end results of the first six months of public access cable television (CATV) channels in New York City were in some ways disappointing. Franchise agreements for each of New York's two CATV systems called for two public-access channels to be in operation by July 1, 1971, one year after the date of the franchise awards. The channels were to be…
Comparing predicted and actual affective responses to process versus outcome: an emotion-as-feedback perspective.

PubMed

Kwong, Jessica Y Y; Wong, Kin Fai Ellick; Tang, Suki K Y

2013-10-01

One of the conjectures in affective forecasting literature is that people are advised to discount their anticipated emotions because their forecasts are often inaccurate. The present research distinguishes between emotional reactions to process versus those to outcome, and highlights an alternative view that affective misforecasts could indeed be adaptive to goal pursuit. Using an ultimatum game, Study 1 showed that people overpredicted how much they would regret and be disappointed by the amount of effort they exerted, should the outcomes turned out worse than expected; nonetheless, people could accurately predict their emotional responses to unfavorable outcomes per se. In a natural setting of a university examination, Study 2 demonstrated that actual regret and disappointment toward favorable outcomes were more intense than the level people expected, but this discrepancy was not observed in their emotional responses to efforts they had invested. These two distinct patterns of results substantiate the argument that the deviation between predicted and actual emotions is dependent on the referents of the emotional reactions. Copyright © 2013 Elsevier B.V. All rights reserved.
Indirect scaling methods for testing quantitative emotion theories.

PubMed

Junge, Martin; Reisenzein, Rainer

2013-01-01

Two studies investigated the utility of indirect scaling methods, based on graded pair comparisons, for the testing of quantitative emotion theories. In Study 1, we measured the intensity of relief and disappointment caused by lottery outcomes, and in Study 2, the intensity of disgust evoked by pictures, using both direct intensity ratings and graded pair comparisons. The stimuli were systematically constructed to reflect variables expected to influence the intensity of the emotions according to theoretical models of relief/disappointment and disgust, respectively. Two probabilistic scaling methods were used to estimate scale values from the pair comparison judgements: Additive functional measurement (AFM) and maximum likelihood difference scaling (MLDS). The emotion models were fitted to the direct and indirect intensity measurements using nonlinear regression (Study 1) and analysis of variance (Study 2). Both studies found substantially improved fits of the emotion models for the indirectly determined emotion intensities, with their advantage being evident particularly at the level of individual participants. The results suggest that indirect scaling methods yield more precise measurements of emotion intensity than rating scales and thereby provide stronger tests of emotion theories in general and quantitative emotion theories in particular.
Amyloid beta (Aβ) peptide modulators and other current treatment strategies for Alzheimer’s disease (AD)

PubMed Central

Lukiw, Walter J.

2012-01-01

Introduction Alzheimer’s disease (AD) is a common, progressive neurological disorder whose incidence is reaching epidemic proportions. The prevailing ‘amyloid cascade hypothesis’, which maintains that the aberrant proteolysis of beta-amyloid precursor protein (βAPP) into neurotoxic amyloid beta (Aβ)-peptides is central to the etiopathology of AD, continues to dominate pharmacological approaches to the clinical management of this insidious disorder. This review is a compilation and update on current pharmacological strategies designed to down-regulate Aβ42-peptide generation in an effort to ameliorate the tragedy of AD. Areas Covered This review utilized on-line data searches at various open online-access websites including the Alzheimer Association, Alzheimer Research Forum; individual drug company databases; the National Institutes of Health (NIH) Medline; Pharmaprojects database; Scopus; inter-University research communications and unpublished research data. Expert Opinion Aβ immunization-, anti-acetylcholinesterase-, β-secretase-, chelation-, γ-secretase-, N-methyl D-aspartate (NMDA) receptor antagonist-, statin-based and other strategies to modulate βAPP processing have dominated pharmacological approaches directed against AD-type neurodegenerative pathology. Cumulative clinical results of these efforts remain extremely disappointing, and have had little overall impact on the clinical management of AD. While a number of novel approaches are in consideration and development, to date there is still no effective treatment or cure for this expanding healthcare concern. PMID:22439907
"I couldn't do this with opposition from my colleagues": A qualitative study of physicians' experiences as clinical tutors

PubMed Central

2011-01-01

Background Clinical contact in the early curriculum and workplace learning with active tutorship are important parts of modern medical education. In a previously published study, we found that medical students' tutors experienced a heavier workload, less reasonable demands and less encouragement, than students. The aim of this interview study was to further illuminate physicians' experiences as clinical tutors. Methods Twelve tutors in the Early Professional Contact course were interviewed. In the explorative interviews, they were asked to reflect upon their experiences of working as tutors in this course. Systematic text condensation was used as the analysis method. Results In the analysis, five main themes of physicians' experiences as clinical tutors in the medical education emerged: (a) Pleasure and stimulation. Informants appreciated tutorship and meeting both students and fellow tutors, (b) Disappointment and stagnation. Occasionally, tutors were frustrated and expressed negative feelings, (c) Demands and duty. Informants articulated an ambition to give students their best; a desire to provide better medical education but also a duty to meet demands of the course management, (d) Impact of workplace relations. Tutoring was made easier when the clinic's management provided active support and colleagues accepted students at the clinic, and (e) Multitasking difficulties. Combining several duties with those of a tutorship was often reported as difficult. Conclusions It is important that tutors' tasks are given adequate time, support and preparation. Accordingly, it appears highly important to avoid multitasking and too heavy a workload among tutors in order to facilitate tutoring. A crucial factor is acceptance and active organizational support from the clinic's management. This implies that tutoring by workplace learning in medical education should play an integrated and accepted role in the healthcare system. PMID:21975057
Clinical Pharmacology and Therapeutics—past, present and future

PubMed Central

Reid, John L.

1997-01-01

Aims To obtain information about the speciality of clinical pharmacology and therapeutics in the United Kingdom. Methods A survey of the views of 26 individuals in academic posts in clinical pharmacology and therapeutics was carried out by postal questionnaire. Response rate was 100%. Results Of 25 assessable responses of 25 centres, there were 35 academic staff of professorial status (median 2, range 0–5) and 61 staff of reader/senior lecturer status (median 2, range 0–5) but only 20 clinical staff in training grades in 19 institutions. All had extensive clinical commitments. Two-thirds of respondents considered that the speciality was stable locally and nationally. However, recruitment of trainees was poor with only 8% of responders having several good applicants for each post and 90% reported that recruitment had deteriorated in the last 5–10 years. Likely good future careers for clinical pharmacologists in training were considered by 75–80% of respondents to likely lie in the pharmaceutical industry or regulatory authorities. Greater flexibility is required to facilitate training in clinical pharmacology and therapeutics. Conclusions Clincal pharmacology and therapeutics in the United Kingdom has a strong academic base but a sub-optimal age structure. Recent experience in recruitment into training posts was disappointing. This may reflect wider problems of recruitment into academic medicine in this country. PMID:9241105
Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure.

PubMed

Hartman, Minke H T; Groot, Hilde E; Leach, Irene Mateo; Karper, Jacco C; van der Harst, Pim

2018-02-15

Many cytokines are currently under investigation as potential target to improve cardiac function and outcome in the setting of acute myocardial infarction (MI) or chronic heart failure (HF). Here we aim to provide a translational overview of cytokine inhibiting therapies tested in experimental models and clinical studies. In various experimental studies, inhibition of interleukin-1 (IL-1), -6 (IL-6), -8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), CC- and CXC chemokines, and tumor necrosis factor-α (TNF-α) had beneficial effects on cardiac function and outcome. On the other hand, neutral or even detrimental results have been reported for some (IL-1, IL-6, IL-8, and MCP-1). Ambivalence of cytokine function, differences in study designs, treatment regimens and chosen endpoints hamper the translation of experimental research into clinical practice. Human studies are currently limited to IL-1β inhibition, IL-1 receptor antagonists (IL-1RA), IL-6 receptor antagonists (IL-6RA) or TNF inhibition. Despite favorable effects on cardiovascular events observed in retrospective cohort studies of rheumatoid arthritis patients treated with TNF inhibition or IL-1RA, most prospective studies reported disappointing and inconsistent results. Smaller studies (n < 100) generally reported favorable results of anticytokine therapy on cardiac function, but only one of the larger studies (n > 100) evaluating IL-1β inhibition presented positive results on outcome. In conclusion, of the 10 anticytokine therapies tested in animals models beneficial effects have been reported in at least one setting. In larger clinical studies, findings were unsatisfactory in all but one. Many anticytokine therapies with promising animal experimental data continue to require further evaluation in humans. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Flexible Positions, Managed Hopes: The Promissory Bioeconomy of a Whole Genome Sequencing Cancer Study

PubMed Central

Haase, Rachel; Michie, Marsha; Skinner, Debra

2015-01-01

Genomic research has rapidly expanded its scope and ambition over the past decade, promoted by both public and private sectors as having the potential to revolutionize clinical medicine. This promissory bioeconomy of genomic research and technology is generated by, and in turn generates, the hopes and expectations shared by investors, researchers and clinicians, patients, and the general public alike. Examinations of such bioeconomies have often focused on the public discourse, media representations, and capital investments that fuel these “regimes of hope,” but also crucial are the more intimate contexts of small-scale medical research, and the private hopes, dreams, and disappointments of those involved. Here we examine one local site of production in a university-based clinical research project that sought to identify novel cancer predisposition genes through whole genome sequencing in individuals at high risk for cancer. In-depth interviews with 24 adults who donated samples to the study revealed an ability to shift flexibly between positioning themselves as research participants on the one hand, and as patients or as family members of patients, on the other. Similarly, interviews with members of the research team highlighted the dual nature of their positions as researchers and as clinicians. For both parties, this dual positioning shaped their investment in the project and valuing of its possible outcomes. In their narratives, all parties shifted between these different relational positions as they managed hopes and expectations for the research project. We suggest that this flexibility facilitated study implementation and participation in the face of potential and probable disappointment on one or more fronts, and acted as a key element in the resilience of this local promissory bioeconomy. We conclude that these multiple dimensions of relationality and positionality are inherent and essential in the creation of any complex economy, “bio” or otherwise. PMID:25697637

Stem cells and their role in renal ischaemia reperfusion injury.

PubMed

Bagul, Atul; Frost, Jodie H; Drage, Martin

2013-01-01

Ischaemia-reperfusion injury (IRI) remains one of the leading causes of acute kidney injury (AKI). IRI is an underlying multifactorial pathophysiological process which affects the outcome in both native and transplanted patients. The high morbidity and mortality associated with IRI/AKI and disappointing results from current available clinical therapeutic approaches prompt further research. Stem cells (SC) are undifferentiated cells that can undergo both renewal and differentiation into one or more cell types which can possibly ameliorate IRI. To carry out a detailed literature analysis and construct a comprehensive literature review addressing the role of SC in AKI secondary to IRI. Evidence favouring the role of SC in renal IRI and evidence showing no benefits of SC in renal IRI are the two main aspects to be studied. The search strategy was based on an extensive search addressing MESH terms and free text terms. The majority of studies in the field of renal IRI and stem cell therapy show substantial benefits. Studies were mostly conducted in small animal models, thus underscoring the need for further pre-clinical studies in larger animal models, and results should be taken with caution. SC therapy may be promising though controversy exists in the exact mechanism. Thorough scientific exploration is required to assess mechanism, safety profile, reproducibility and methods to monitor administered SC. Copyright © 2012 S. Karger AG, Basel.
Small-cell carcinoma of the urinary bladder: where do we stand?

PubMed

Ghervan, Liviu; Zaharie, Andreea; Ene, Bogdan; Elec, Florin I

2017-01-01

Small-cell carcinoma of the urinary bladder is a very rare pathology, but with a very aggressive behavior and disappointing prognosis. The literature concerning this type of cancer is scarce and physicians may encounter difficulty trying to manage it. Most articles involve the study of case series, without definite results due to the small number of patients. The present article aims at gathering the most significant articles and results in order to offer a broad perspective on the existing literature concerning this pathology.
The Importance of Processes and Contexts in Organizational Psychology.

DTIC Science & Technology

1980-09-01

our discipline. A second area of great importance within organizational psychology focuses upon leadership processes and leader behaviors. As we all...know, the study, and more particularly the results produced by the study, of leadership has been a major disappointment for many of us working within...construct validity in the study of leadership . Several authors have recently noted this problem and have suggested that it may be reasonable to be
Influences Determining European Coal Seam Gas Deliverability

NASA Astrophysics Data System (ADS)

Clark, G.

2009-04-01

Technically the coal basins of Europe have generated significant Gas In Place figures that has historically generated investor's interest in the development of this potential coal seam gas (CSG) resource. In the early 1980's, a wave of international, principally American, companies arrived, established themselves, drilled and then left with a poor record of success and disappointed investors. Recently a second wave of investment started after 2002, with the smaller companies leading the charge but have the lesson been learned from the past failures? To select a CSG investment project the common European approach has been to: 1. Find an old mining region; 2. Look to see if it had a coal mine methane gas problem; 3. Look for the non-mined coal seams; and 4. Peg the land. This method is perhaps the reason why the history of CSG exploration in Europe is such a disappointment as generally the coal mining regions of Europe do not have commercial CSG reservoir attributes. As a result, investors and governments have lost confidence that CSG will be a commercial success in Europe. New European specific principles for the determination of commercial CSG prospects have had to be delineated that allow for the selection of coal basins that have a strong technical case for deliverability. This will result in the return of investor confidence.
Fairness decisions in response to emotions: a functional MRI study among criminal justice-involved boys with conduct disorder.

PubMed

Klapwijk, Eduard T; Lelieveld, Gert-Jan; Aghajani, Moji; Boon, Albert E; van der Wee, Nic J A; Popma, Arne; Vermeiren, Robert R J M; Colins, Olivier F

2016-04-01

Research suggests that individuals with conduct disorder (CD) are marked by social impairments, such as difficulties in processing the affective reactions of others. Little is known, though, about how they make decisions during social interactions in response to emotional expressions of others. In this study, we therefore investigated the neural mechanisms underlying fairness decisions in response to communicated emotions of others in aggressive, criminal justice-involved boys with CD (N = 32) compared with typically developing (TD) boys (N = 33), aged 15-19 years. Participants received written emotional responses (angry, disappointed or happy) from peers in response to a previous offer and then had to make fairness decisions in a version of the Dictator Game. Behavioral results showed that CD boys did not make differential fairness decisions in response to the emotions, whereas the TD boys did show a differentiation and also responded more unfair to happy reactions than the CD boys. Neuroimaging results revealed that when receiving happy vs disappointed and angry reactions, the CD boys showed less activation than the TD boys in the temporoparietal junction and supramarginal gyrus, regions involved in perspective taking and attention. These results suggest that boys with CD have difficulties with processing explicit emotional cues from others on behavioral and neural levels. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
Gene therapy for immune disorders: good news tempered by bad news.

PubMed

Puck, Jennifer M; Malech, Harry L

2006-04-01

After a dozen years of human gene therapy trials characterized by minimal gene correction and disappointing clinical impact, the field of gene therapy received some good news in 2000. Infants with X-linked severe combined immunodeficiency who received retroviral gene addition to cells from their bone marrow developed impressive immune reconstitution. During the following 2 years, additional patients were treated and the news was even better-babies receiving gene therapy had sustained T-cell production and in several cases developed better cell function than most patients treated with standard bone marrow transplants. Unfortunately, bad news followed. Three of the patients experienced leukemic T-cell expansions, found to be associated with retroviral insertions into genomic DNA. Where does the field stand today?
Bovine pasteurellosis and other bacterial infections of the respiratory tract.

PubMed

Griffin, Dee

2010-03-01

Despite technological, biologic, and pharmacologic advances the bacterial component of the bovine respiratory disease (BRD) complex continues to have a major adverse effect on the health and wellbeing of stocker and feeder cattle. Overlooked in this disappointing assessment is evaluation of the effects that working with younger, lighter-weight cattle have on managing the bacterial component of the BRD complex. Most problems associated with BRD come from cattle taken from and comingled with cattle operations that have inconsistent or nonexistent cattle health management. This article reviews the biologic, clinical, and management aspects of Pasteurella multocida, Mannheimia haemolytica, Histophilus somni, and Mycoplasma bovis, primarily as related to current production management considerations of stocker and feeder cattle. Copyright 2010 Elsevier Inc. All rights reserved.
[Anxiety disorders in DSM-5].

PubMed

Márquez, Miguel

2014-01-01

The fifth edition of Diagnostic and Statistical Manual, the DSM-5 appeared officially in May 2013 during the development of the 166th Annual Meetingof the American Psychiatric Association (APA) in San Francisco. The drafting process was long and complex; much of the debate became public so that the expectations were great. And it must be said that the new edition did not disappoint, as many changes were made in relation to their predecessors. In Chapter of Anxiety Disorders, which is reviewed in this article, the changes were significant. Obsessive-compulsive disorder and Stress-related disorders were excluded and new clinical pictures, such as separation anxiety disorder and selective mutism, were included. And took place was the long awaited split between panic disorder and agoraphobia, now two separate disorders.
Update on therapeutic management of idiopathic pulmonary fibrosis

PubMed Central

Tzouvelekis, Argyris; Bonella, Francesco; Spagnolo, Paolo

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive diffuse parenchymal lung disease of unknown origin, with a mortality rate exceeding that of many cancers. The diagnostic process is complex and relies on the clinician integrating clinical, laboratory, radiological, and histological data. In the last decade, major advances in our understanding of the pathogenesis of IPF have shifted the paradigm from a primarily inflammatory process evolving to fibrosis to a condition driven by aberrant wound healing following alveolar epithelial cell injury that results in scarring of the lung, architectural distortion, and irreversible loss of function. Improved understanding of disease pathogenesis has led to the identification of several therapeutic targets and the design of high-quality clinical trials evaluating novel compounds. However, the results of these studies have been mostly disappointing, probably due to the plethora of mediators, growth factors, and signaling pathways involved in the fibrotic process. Most recently, pirfenidone and nintedanib, two compounds with pleiotropic anti-fibrotic properties, have been proven effective in reducing functional decline and disease progression in IPF. This is a major breakthrough. Nevertheless, we still have a long way to go. In fact, neither pirfenidone nor nintedanib is a cure for IPF, and most patients continue to progress despite treatment. As such, comprehensive care of patients with IPF, including management of concomitant conditions and physical debility, as well as timely referral for lung transplantation, remains essential. Several agents with a high potential are currently being tested, and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF. PMID:25767391
The role of angiotensin receptor-neprilysin inhibitors in cardiovascular disease-existing evidence, knowledge gaps, and future directions.

PubMed

Ambrosy, Andrew P; Mentz, Robert J; Fiuzat, Mona; Cleland, John G F; Greene, Stephen J; O'Connor, Christopher M; Teerlink, John R; Zannad, Faiez; Solomon, Scott D

2018-02-21

Although traditional renin-angiotensin system antagonists including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have revolutionized the treatment of cardiovascular disease (CVD), the pivotal PARADIGM-HF trial demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was superior to an angiotensin-converting enzyme inhibitor in reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction. However, despite international regulatory approval and strong recommendations in the guidelines, uptake of sacubitril/valsartan has been disappointing. Sacubitril/valsartan is now the focus of a large programme of clinical trials testing the hypothesis that ARNIs may supplant conventional renin-angiotensin system inhibitors across the spectrum of CVD, including hypertension, secondary prevention after myocardial infarction, and heart failure with preserved ejection fraction. This review summarizes the existing evidence, knowledge gaps, and future directions of ARNIs in CVD based on discussions between clinical trialists, industry representatives, and regulatory authorities at the 2016 Global CardioVascular Clinical Trialists Forum in Washington, D.C. © 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.
Intravenous immunoglobulin in neurology--mode of action and clinical efficacy.

PubMed

Lünemann, Jan D; Nimmerjahn, Falk; Dalakas, Marinos C

2015-02-01

Intravenous immunoglobulin (IVIg)-a preparation of polyclonal serum IgG pooled from thousands of blood donors-has been used for nearly three decades, and is proving to be an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological diseases. Evidence from controlled clinical trials has established IVIg as a first-line therapy for Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. IVIg is also an effective rescue therapy in some patients with worsening myasthenia gravis, and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. IVIg has been tested in some neurodegenerative disorders, but a controlled study in Alzheimer disease yielded disappointing results. Despite its widespread use and therapeutic success, the mechanisms of action of IVIg are poorly understood. Several hypotheses, based on the function of either the variable or constant IgG fragments, have been proposed to explain IVIg's immunomodulatory activity. This Review highlights emerging data on the mechanisms of action of IVIg related to its anti-inflammatory activity, especially that involving the cellular Fcγ receptors and Fc glycosylation. We also summarize recent trials in neurological diseases, discuss potential biomarkers of efficacy, offer practical guidelines on administration, and provide a rationale for experimental trials in neuroinflammatory disorders.
The intelligent, painless, "germ-free" colonoscopy: A Columbus' egg for increasing population adherence to colorectal cancer screening?

PubMed

Perri, Francesco; Iacobellis, Angelo; Gentile, Marco; Tumino, Emanuele; Andriulli, Angelo

2010-12-01

Colorectal cancer (CRC) represents a major cause of morbidity and mortality. Although it is widely accepted that CRC screening in average risk populations lowers CRC incidence and mortality, a disappointedly low adherence rate to both faecal occult blood testing and colonoscopy-based screening programs has been observed in Italy and in other European countries. Main reasons for the low acceptance of colonoscopy-based CRC screening has been ascribed to lack of recommendations given by general practitioners, fear of discomfort or complications, embarrassment, and avoidance of unpleasant preparation. New advances in endoscopic technology such as colon capsule and robotic colonoscopy might represent the ideal tool for CRC screening since they reduce or eliminate procedure-related pain and discomfort. Moreover, no disinfection between procedures is required. Motion of the new probes along the gastrointestinal tract is achieved either in passive modality by utilizing the gut peristalsis (colon capsule) or in active "intelligent" modality by means of computer-assisted propulsion (robotic colonoscopy). In this review, the preliminary clinical results obtained with the new devices are summarized. It is expected that the new instruments will be soon available in clinical practice with the hope of increasing adherence to CRC screening programs. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Helminths and Immunological Tolerance

PubMed Central

Johnston, Chris J.C.; McSorley, Henry J.; Anderton, Stephen M.; Wigmore, Stephen J.; Maizels, Rick M.

2014-01-01

Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world’s population. It is now well established that the parasites’ success is the result of active immunomodulation of their hosts’ immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice. PMID:24025322
Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence

PubMed Central

Dürsteler, Kenneth M; Berger, Eva-Maria; Strasser, Johannes; Caflisch, Carlo; Mutschler, Jochen; Herdener, Marcus; Vogel, Marc

2015-01-01

Background Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. Aim To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. Methods We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. Results MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. Conclusion Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research. PMID:26124696
Operative Treatment of the Insertional Achilles Tendinopathy Through a Transtendinous Approach.

PubMed

Ettinger, Sarah; Razzaq, Rameez; Waizy, Hazibullah; Claassen, Leif; Daniilidis, Kiriakos; Stukenborg-Colsman, Christina; Plaass, Christian

2016-03-01

Different operative techniques have been proposed for the treatment of insertional Achilles tendinopathy (IAT), with often disappointing results. The aim of this study was to evaluate the outcome of the transtendinous approach in IAT. Forty patients operated with an IAT between 2010 and 2011 were included in this retrospective study. The mean follow-up was 15.6 (±3.7, 12-27) months. Indication for surgery was IAT with failed conservative therapy. Using a transtendinous approach, the Achilles tendon (AT) was partially detached and all pathologic tissues were debrided. The AT was reinserted using different anchor techniques. Clinical data were recorded using examination and clinical scores (American Orthopaedic Foot & Ankle Society [AOFAS], Foot and Ankle Outcome Score [FAOS], Numerical Rating Scale [NRS], and Short Form-36 [SF-36]). The mean AOFAS hindfoot score improved from 59.4 preoperatively to 86.5 postoperatively (P < .05). All FAOS subscales, NRS pain scores, and pain and function subscales of SF-36 improved significantly. The median time of return to work and sports was 14.5 (±17.6; 2-82) and 22.7 (±13.4; 7-58) weeks. Three patients had superficial wound healing difficulties but required no revision. One patient had to be revised due to a hematoma. Patients treated with 2 suture anchors or double-row fixation technique improved significantly (P < .05) compared to those with single anchor fixation, regarding AOFAS score (79.6 and 90.2) and FAOS subscale scores. Eighty-three percent of the patients showed good to excellent results. The transtendinous approach allowed access to all associated pathologies in IAT. It had relatively few complications and lead to good clinical results. Level IV, retrospective case series. © The Author(s) 2015.
Spider Silk Constructs Enhance Axonal Regeneration and Remyelination in Long Nerve Defects in Sheep

PubMed Central

Radtke, Christine; Allmeling, Christina; Waldmann, Karl-Heinz; Reimers, Kerstin; Thies, Kerstin; Schenk, Henning C.; Hillmer, Anja; Guggenheim, Merlin; Brandes, Gudrun; Vogt, Peter M.

2011-01-01

Background Surgical reapposition of peripheral nerve results in some axonal regeneration and functional recovery, but the clinical outcome in long distance nerve defects is disappointing and research continues to utilize further interventional approaches to optimize functional recovery. We describe the use of nerve constructs consisting of decellularized vein grafts filled with spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect in adult sheep. Methodology/Principal Findings The nerve constructs were compared to autologous nerve grafts. Regeneration was evaluated for clinical, electrophysiological and histological outcome. Electrophysiological recordings were obtained at 6 months and 10 months post surgery in each group. Ten months later, the nerves were removed and prepared for immunostaining, electrophysiological and electron microscopy. Immunostaining for sodium channel (NaV 1.6) was used to define nodes of Ranvier on regenerated axons in combination with anti-S100 and neurofilament. Anti-S100 was used to identify Schwann cells. Axons regenerated through the constructs and were myelinated indicating migration of Schwann cells into the constructs. Nodes of Ranvier between myelin segments were observed and identified by intense sodium channel (NaV 1.6) staining on the regenerated axons. There was no significant difference in electrophysiological results between control autologous experimental and construct implantation indicating that our construct are an effective alternative to autologous nerve transplantation. Conclusions/Significance This study demonstrates that spider silk enhances Schwann cell migration, axonal regrowth and remyelination including electrophysiological recovery in a long-distance peripheral nerve gap model resulting in functional recovery. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery. PMID:21364921
Manifest dream content as a possible predictor of suicidality.

PubMed

Glucksman, Myron L

2014-12-01

The prediction of suicidal intent remains a clinical problem. This presentation illustrates that a distinction may be made between the manifest dream reports of patients who are potentially or acutely suicidal and those who are not. A review of the literature reveals that the manifest dream reports of clinically depressed, non-suicidal individuals differ from those who are depressed and acutely suicidal. The former contain themes of loss, disappointment, rejection, helplessness, hopelessness, failure, and death. The latter contain themes of dying, death, destruction, and violence directed toward the dreamer or others, as well as hopelessness and helplessness. The author collected manifest dream reports from three clinically depressed, non-suicidal patients and three clinically depressed, potentially or acutely suicidal patients. There are apparent differences between the themes of manifest dream reports in the clinically depressed, non-suicidal patients and the clinically depressed, potentially or acutely suicidal patients. The former contain themes of death, loss, rejection, vulnerability, hopelessness, and helplessness. The latter contain themes of active harm or violence (specifically toward the dreamer), dying or being dead, aloneness, vulnerability, hopelessness, and helplessness. Clinical cases and corresponding manifest dream reports are presented. Although this is a preliminary study, it is possible that manifest dream content may be used as one of the predictors of suicidality, in conjunction with latent dream content, diagnosis, life circumstance, and clinical status.
Nordic couples' decision-making processes during assisted reproduction treatments.

PubMed

Sol Olafsdottir, Helga; Wikland, Matts; Möller, Anders

2013-06-01

To study couples' perceptions of their decision-making process during the first three years of infertility treatments. This study is a part of a larger project studying the decision-making processes of 22 infertile heterosexual couples, recruited from fertility clinics in all five Nordic countries, over a three year period. A descriptive qualitative method was used. Process of decision-making during assisted reproduction treatments. Seventeen couples had succeeded in becoming parents after approximately three years. Our study suggests that the decision-making process during fertility treatments has three phases: (i) recognizing the decisions to be made, with subcategories; the driving force, mutual project, (ii) gathering knowledge and experience about the options, with subcategories; trust, patient competence, personalized support, and (iii) adapting decisions to possible options, with subcategories; strategic planning, adaption. The core category was "maintaining control in a situation of uncertainty." Two parallel processes affect couples' decision-making process, one within themselves and their relationship, and the other in their contact with the fertility clinic. Couples struggle to make decisions, trusting clinic personnel for guidance, knowledge, and understanding. Nevertheless, couples expressed disappointment with the clinics' reactions to their requests for shared decision-making. Copyright © 2013 Elsevier B.V. All rights reserved.
Improvements in Empirical Modelling of the World-Wide Ionosphere

DTIC Science & Technology

1986-10-31

The fact that the world-wide distribution of the basic inputs is far from being uniform forced Gallet and Jones to develop . a special procedure for...made the result more reasonable, it had a disappointing effect on the latitudinal variation over the oceans. Feeling that shifting along circles of...range. Ano- ther vertical profile model is used in the Bent-model4 which is applied in NASA practice for computing the different effects of
Sin(x)**2 + cos(x)**2 = 1. [programming identities using comparative combinatorial substitutions

NASA Technical Reports Server (NTRS)

Stoutemyer, D. R.

1977-01-01

Attempts to achieve tasteful automatic employment of the identities sin sq x + cos sq x = 1 and cos sq h x -sin sq h x = 1 in a manner which truly minimizes the complexity of the resulting expression are described. The disappointments of trigonometric reduction, trigonometric expansion, pattern matching, Poisson series, and Demoivre's theorem are related. The advantages of using the method of comparative combinatorial substitutions are illustrated.

A caution to Native American institutional review boards about scientism and censorship.

PubMed

Askland, Andrew

2002-01-01

Native American Institutional Review Boards (IRBs) promote the health and welfare of tribes by reviewing protocols for research studies that focus on their tribes. The benefits of approved protocols should not be overstated lest good studies disappoint because they do not satisfy unachievable expectations. IRBs also should avoid the temptation to censor the outcomes of those studies. Science relies on candor and clarity about results and methods to move forward.
Excerpts from the 1st international NTNU symposium on current and future clinical biomarkers of cancer: innovation and implementation, June 16th and 17th 2016, Trondheim, Norway.

PubMed

Robles, Ana I; Olsen, Karina Standahl; Tsui, Dana W T; Georgoulias, Vassilis; Creaney, Jenette; Dobra, Katalin; Vyberg, Mogens; Minato, Nagahiro; Anders, Robert A; Børresen-Dale, Anne-Lise; Zhou, Jianwei; Sætrom, Pål; Nielsen, Boye Schnack; Kirschner, Michaela B; Krokan, Hans E; Papadimitrakopoulou, Vassiliki; Tsamardinos, Ioannis; Røe, Oluf D

2016-10-19

The goal of biomarker research is to identify clinically valid markers. Despite decades of research there has been disappointingly few molecules or techniques that are in use today. The "1st International NTNU Symposium on Current and Future Clinical Biomarkers of Cancer: Innovation and Implementation", was held June 16th and 17th 2016, at the Knowledge Center of the St. Olavs Hospital in Trondheim, Norway, under the auspices of the Norwegian University of Science and Technology (NTNU) and the HUNT biobank and research center. The Symposium attracted approximately 100 attendees and invited speakers from 12 countries and 4 continents. In this Symposium original research and overviews on diagnostic, predictive and prognostic cancer biomarkers in serum, plasma, urine, pleural fluid and tumor, circulating tumor cells and bioinformatics as well as how to implement biomarkers in clinical trials were presented. Senior researchers and young investigators presented, reviewed and vividly discussed important new developments in the field of clinical biomarkers of cancer, with the goal of accelerating biomarker research and implementation. The excerpts of this symposium aim to give a cutting-edge overview and insight on some highly important aspects of clinical cancer biomarkers to-date to connect molecular innovation with clinical implementation to eventually improve patient care.
On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics

PubMed Central

Dimberg, Lina Y.; Anderson, Charles K.; Camidge, Ross; Behbakht, Kian; Thorburn, Andrew; Ford, Heide L.

2015-01-01

TRAIL and agonistic antibodies against TRAIL death receptors kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL death receptors in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity. PMID:22580613
Just tell me what you want!: the promise and perils of rapid prototyping with the World Wide Web.

PubMed

Cimino, J J; Socratous, S A

1996-01-01

Construction of applications using the World Wide Web architecture and Hypertext Markup Language (HTML) documents is relatively simple. We are exploring this approach with an application, called PolyMed now in use by surgical residents for one year. We monitored use and obtained user feedback to develop new features and eliminate undesirable ones. The system has been used to keep track of over 4,200 patients. We predicted, several advantages and disadvantages to this approach to prototyping clinical applications. Our experience confirms some advantages (ease of development and customization, ability to exploit non-Web system components, and simplified user interface design) and disadvantages (lack of database management services). Some predicted disadvantages failed to materialize (difficulty modeling a clinical application with hypertext and inconveniences associated with the "connectionless" nature of the Web). We were disappointed to find that while integration of external Web applications (such as Medline) into our application was easy, our users did not find it useful.
Current status of new tuberculosis vaccine in children

PubMed Central

Pang, Yu; Zhao, Aihua; Cohen, Chad; Kang, Wanli; Lu, Jie; Wang, Guozhi; Zhao, Yanlin; Zheng, Suhua

2016-01-01

ABSTRACT Pediatric tuberculosis contributes significantly to the burden of TB disease worldwide. In order to achieve the goal of eliminating TB by 2050, an effective TB vaccine is urgently needed to prevent TB transmission in children. BCG vaccination can protect children from the severe types of TB such as TB meningitis and miliary TB, while its efficacy against pediatric pulmonary TB ranged from no protection to very high protection. In recent decades, multiple new vaccine candidates have been developed, and shown encouraging safety and immunogenicity in the preclinical experiments. However, the limited data on protective efficacy in infants evaluated by clinical trials has been disappointing, an example being MVA85A. To date, no vaccine has been shown to be clinically safer and more effective than the presently licensed BCG vaccine. Hence, before a new vaccine is developed with more promising efficacy, we must reconsider how to better use the current BCG vaccine to maximize its effectiveness in children. PMID:27002369
Just tell me what you want!: the promise and perils of rapid prototyping with the World Wide Web.

PubMed Central

Cimino, J. J.; Socratous, S. A.

1996-01-01

Construction of applications using the World Wide Web architecture and Hypertext Markup Language (HTML) documents is relatively simple. We are exploring this approach with an application, called PolyMed now in use by surgical residents for one year. We monitored use and obtained user feedback to develop new features and eliminate undesirable ones. The system has been used to keep track of over 4,200 patients. We predicted, several advantages and disadvantages to this approach to prototyping clinical applications. Our experience confirms some advantages (ease of development and customization, ability to exploit non-Web system components, and simplified user interface design) and disadvantages (lack of database management services). Some predicted disadvantages failed to materialize (difficulty modeling a clinical application with hypertext and inconveniences associated with the "connectionless" nature of the Web). We were disappointed to find that while integration of external Web applications (such as Medline) into our application was easy, our users did not find it useful. PMID:8947759
The case for intrauterine stem cell transplantation.

PubMed

Mattar, Citra N; Biswas, Arijit; Choolani, Mahesh; Chan, Jerry K Y

2012-10-01

The clinical burden imposed by the collective group of monogenic disorders demands novel therapies that are effective at achieving phenotypic cure early in the disease process before the development of permanent organ damage. This is important for lethal diseases and also for non-perinatally lethal conditions that are characterised by severe disability with little prospect of postnatal cure. Where postnatal treatments are limited to palliative options, intrauterine stem-cell therapies may offer the potential to arrest pathogenesis in the early undamaged fetus. Intrauterine stem-cell transplantation has been attempted for a variety of diseases, but has only been successful in immune deficiency states in the presence of a competitive advantage for donor cells. This disappointing clinical record requires preclinical investigations into strategies that improve donor cell engraftment, including optimising the donor cell source and manipulating the microenvironment to facilitate homing. This chapter aims to outline the current challenges of intrauterine stem-cell therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.
Capital projects: Egypt case study. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lieberson, J.; Stallard, J.

1994-03-01

This report assesses the US Agency for International Development`s (A.I.D.`s) capital assistance program in Egypt in terms of both its commercial benefits for the United States and its developmental benefits for Egypt. In regard to the first aspect, the study found that few A.I.D.-funded projects or studies generated either participation by other donors or follow-on sales for U.S. companies. The report places much of the blame for this on U.S. firms` failure to take advantage of a clear opportunity to develop the Egyptian commercial market. Findings regarding the developmental benefits of the projects are mixed. (1) The projects helped supportmore » strong private sector growth in Egypt through the 1980`s. Nonetheless, their economic and financial rates of return were generally disappointing. (2) The projects were built to a high technical standard, but their sustainability is in doubt. (3) The pursuit of commercial advantage for U.S. firms did not distort the developmental goals of the projects. Overall, the report attributes the disappointing economic results of A.I.D.`s capital assistance program to a poor policy environment, which the reforms pursued in connection with the program did little to change.« less
Echocardiography and cardiac resynchronisation therapy, friends or foes?

PubMed

van Everdingen, W M; Schipper, J C; van 't Sant, J; Ramdat Misier, K; Meine, M; Cramer, M J

2016-01-01

Echocardiography is used in cardiac resynchronisation therapy (CRT) to assess cardiac function, and in particular left ventricular (LV) volumetric status, and prediction of response. Despite its widespread applicability, LV volumes determined by echocardiography have inherent measurement errors, interobserver and intraobserver variability, and discrepancies with the gold standard magnetic resonance imaging. Echocardiographic predictors of CRT response are based on mechanical dyssynchrony. However, parameters are mainly tested in single-centre studies or lack feasibility. Speckle tracking echocardiography can guide LV lead placement, improving volumetric response and clinical outcome by guiding lead positioning towards the latest contracting segment. Results on optimisation of CRT device settings using echocardiographic indices have so far been rather disappointing, as results suffer from noise. Defining response by echocardiography seems valid, although re-assessment after 6 months is advisable, as patients can show both continuous improvement as well as deterioration after the initial response. Three-dimensional echocardiography is interesting for future implications, as it can determine volume, dyssynchrony and viability in a single recording, although image quality needs to be adequate. Deformation patterns from the septum and the derived parameters are promising, although validation in a multicentre trial is required. We conclude that echocardiography has a pivotal role in CRT, although clinicians should know its shortcomings.
N-Acetylcysteine's Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements.

PubMed

Chertoff, Jason

2018-02-01

To review the data surrounding the utility of N-acetylcysteine (NAC) in sepsis and identify areas needed for additional research. A review of articles describing the mechanisms of action and clinical use of NAC in sepsis. Despite many advances in critical care medicine, still as many as 50% of patients with septic shock die. Treatments thus far have focused on resuscitation and restoration of macrocirculatory targets in the early phases of sepsis, with less focus on microcirculatory dysfunction. N-acetylcysteine, due to its anti-inflammatory and antioxidative properties, has been readily investigated in sepsis and has yielded largely incongruous and disappointing results. In addition to its known anti-inflammatory and antioxidative roles, one underappreciated property of NAC is its ability to vasodilate the microcirculation and improve locoregional blood flow. Some investigators have sought to capitalize on this mechanism with promising results, as evidenced by microcirculatory vasodilation, improvements in regional blood flow and oxygen delivery, and reductions in lactic acidosis, organ failure, and mortality. In addition to its antioxidant and anti-inflammatory properties, N-acetylcysteine possesses vasodilatory properties that could benefit the microcirculation in sepsis. It is imperative that we investigate these properties to uncover NAC's full potential for benefit in sepsis.
Facial and occlusal esthetic improvements of an adult skeletal Class III malocclusion using surgical, orthodontic, and implant treatment

PubMed Central

de Almeida Cardoso, Mauricio; de Avila, Erica Dorigatti; Guedes, Fabio Pinto; Battilani Filho, Valter Antonio Ban; Capelozza Filho, Leopoldino; Correa, Marcio Aurelio; Nary Filho, Hugo

2016-01-01

The aim of this clinical report is to describe the complex treatment of an adult Class III malocclusion patient who was disappointed with the outcome of a previous oral rehabilitation. Interdisciplinary treatment planning was performed with a primary indication for implant removal because of marginal bone loss and gingival recession, followed by orthodontic and surgical procedures to correct the esthetics and skeletal malocclusion. The comprehensive treatment approach included: (1) implant removal in the area of the central incisors; (2) combined orthodontic decompensation with mesial displacement and forced extrusion of the lateral incisors; (3) extraction of the lateral incisors and placement of new implants corresponding to the central incisors, which received provisional crowns; (4) orthognathic surgery for maxillary advancement to improve occlusal and facial relationships; and finally, (5) orthodontic refinement followed by definitive prosthetic rehabilitation of the maxillary central incisors and reshaping of the adjacent teeth. At the three-year follow-up, clinical and radiographic examinations showed successful replacement of the central incisors and improved skeletal and esthetic appearances. Moreover, a Class II molar relationship was obtained with an ideal overbite, overjet, and intercuspation. In conclusion, we report the successful esthetic anterior rehabilitation of a complex case in which interdisciplinary treatment planning improved facial harmony, provided gingival architecture with sufficient width and thickness, and improved smile esthetics, resulting in enhanced patient comfort and satisfaction. This clinical case report might be useful to improve facial esthetics and occlusion in patients with dentoalveolar and skeletal defects. PMID:26877982
Parastomal hernias after radical cystectomy and ileal conduit diversion

PubMed Central

Donahue, Timothy F.

2016-01-01

Parastomal hernia, defined as an "incisional hernia related to an abdominal wall stoma", is a frequent complication after conduit urinary diversion that can negatively impact quality of life and present a clinically significant problem for many patients. Parastomal hernia (PH) rates may be as high as 65% and while many patients are asymptomatic, in some series up to 30% of patients require surgical intervention due to pain, leakage, ostomy appliance problems, urinary obstruction, and rarely bowel obstruction or strangulation. Local tissue repair, stoma relocation, and mesh repairs have been performed to correct PH, however, long-term results have been disappointing with recurrence rates of 30%–76% reported after these techniques. Due to high recurrence rates and the potential morbidity of PH repair, efforts have been made to prevent PH development at the time of the initial surgery. Randomized trials of circumstomal prophylactic mesh placement at the time of colostomy and ileostomy stoma formation have shown significant reductions in PH rates with acceptably low complication profiles. We have placed prophylactic mesh at the time of ileal conduit creation in patients at high risk for PH development and found it to be safe and effective in reducing the PH rates over the short-term. In this review, we describe the clinical and radiographic definitions of PH, the clinical impact and risk factors associated with its development, and the use of prophylactic mesh placement for patients undergoing ileal conduit urinary diversion with the intent of reducing PH rates. PMID:27437533
Small-cell carcinoma of the urinary bladder: where do we stand?

PubMed Central

GHERVAN, LIVIU; ZAHARIE, ANDREEA; ENE, BOGDAN; ELEC, FLORIN I.

2017-01-01

Small-cell carcinoma of the urinary bladder is a very rare pathology, but with a very aggressive behavior and disappointing prognosis. The literature concerning this type of cancer is scarce and physicians may encounter difficulty trying to manage it. Most articles involve the study of case series, without definite results due to the small number of patients. The present article aims at gathering the most significant articles and results in order to offer a broad perspective on the existing literature concerning this pathology. PMID:28246491
[Pelvic floor and pregnancy].

PubMed

Fritel, X

2010-05-01

Congenital factor, obesity, aging, pregnancy and childbirth are the main risk factors for female pelvic floor disorders (urinary incontinence, anal incontinence, pelvic organ prolapse, dyspareunia). Vaginal delivery may cause injury to the pudendal nerve, the anal sphincter, or the anal sphincter. However the link between these injuries and pelvic floor symptoms is not always determined and we still ignore what might be the ways of prevention. Of the many obstetrical methods proposed to prevent postpartum symptoms, episiotomy, delivery in vertical position, delayed pushing, perineal massage, warm pack, pelvic floor rehabilitation, results are disappointing or limited. Caesarean section is followed by less postnatal urinary incontinence than vaginal childbirth. However this difference tends to disappear with time and following childbirth. Limit the number of instrumental extractions and prefer the vacuum to forceps could reduce pelvic floor disorders after childbirth. Ultrasound examination of the anal sphincter after a second-degree perineal tear is useful to detect and repair infra-clinic anal sphincter lesions. Scientific data is insufficient to justify an elective cesarean section in order to avoid pelvic floor symptoms in a woman without previous disorders. Copyright 2010 Elsevier Masson SAS. All rights reserved.
Sepsis and septic shock

PubMed Central

Hotchkiss, Richard S.; Moldawer, Lyle L.; Opal, Steven M.; Reinhart, Konrad; Turnbull, Isaiah R.; Vincent, Jean-Louis

2017-01-01

For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15–25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30–50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental. PMID:28117397
Nitric oxide pathology and therapeutics in sickle cell disease.

PubMed

Kim-Shapiro, Daniel B; Gladwin, Mark T

2018-01-01

Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions which leads to red blood cell (RBC) distortion, calcium-influx mediated RBC dehydration, increased RBC adhesivity, reduced RBC deformability, increased RBC fragility, and hemolysis. These impairments in RBC structure and function result in multifaceted downstream pathology including inflammation, endothelial cell activation, platelet and leukocyte activation and adhesion, and thrombosis, all of which contribute vascular occlusion and substantial morbidity and mortality. Hemoglobin released upon RBC hemolysis scavenges nitric oxide (NO) and generates reactive oxygen species (ROS) and thereby decreases bioavailability of this important signaling molecule. As the endothelium-derived relaxing factor, NO acts as a vasodilator and also decreases platelet, leukocyte, and endothelial cell activation. Thus, low NO bioavailability contributes to pathology in sickle cell disease and its restoration could serve as an effective treatment. Despite its promise, clinical trials based on restoring NO bioavailability have so far been mainly disappointing. However, particular "NO donating" agents such as nitrite, which unlike some other NO donors can improve sickle RBC properties, may yet prove effective.
What is wrong with orphan drug policies?

PubMed

Côté, André; Keating, Bernard

2012-12-01

The effects of orphan drug policies raise serious concerns among payer organizations and lead to often-tragic disappointment for patients who are denied much anticipated drug reimbursements. We evaluate the effects of orphan drug policies on the basis of this concern for real accessibility to drugs. We highlight two unforeseen effects of orphan drug policies: 1) they provide unique business opportunities for manufacturers and 2) drugs approved through these policies are often inaccessible because of their high price. We identify six causes of this emergence of effects. The first four are the direct result of incentives included in orphan drug policies. The fifth cause is the "off-label" use of orphan drugs. These emergent effects have several implications: 1) they raise doubts about the equity of access to drugs, 2) they highlight the limitations of the cohort paradigm in medicine, and c) they force third-party payers to make drugs accessible even when the prices of drugs are believed to be disproportionate to the clinical effects obtained. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.
Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.

PubMed

Frentzas, Sophia; Simoneau, Eve; Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Kostaras, Eleftherios; Nathan, Mark; Wotherspoon, Andrew; Gao, Zu-Hua; Shi, Yu; Van den Eynden, Gert; Daley, Frances; Peckitt, Clare; Tan, Xianming; Salman, Ayat; Lazaris, Anthoula; Gazinska, Patrycja; Berg, Tracy J; Eltahir, Zak; Ritsma, Laila; Van Rheenen, Jacco; Khashper, Alla; Brown, Gina; Nystrom, Hanna; Sund, Malin; Van Laere, Steven; Loyer, Evelyne; Dirix, Luc; Cunningham, David; Metrakos, Peter; Reynolds, Andrew R

2016-11-01

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.
The threshold hypothesis: solving the equation of nurture vs nature in type 1 diabetes.

PubMed

Wasserfall, C; Nead, K; Mathews, C; Atkinson, M A

2011-09-01

For more than 40 years, the contributions of nurture (i.e. the environment) and nature (i.e. genetics) have been touted for their aetiological importance in type 1 diabetes. Disappointingly, knowledge gains in these areas, while individually successful, have to a large extent occurred in isolation from each other. One reason underlying this divide is the lack of a testable model that simultaneously considers the contributions of genetic and environmental determinants in the formation of this and potentially other disorders that are subject to these variables. To address this void, we have designed a model based on the hypothesis that the aetiological influences of genetics and environment, when evaluated as intersecting and reciprocal trend lines based on odds ratios, result in a method of concurrently evaluating both facets and defining the attributable risk of clinical onset of type 1 diabetes. The model, which we have elected to term the 'threshold hypothesis', also provides a novel means of conceptualising the complex interactions of nurture with nature in type 1 diabetes across various geographical populations.
Targeting oxidant-dependent mechanisms for the treatment of respiratory diseases and their comorbidities.

PubMed

Thomson, Neil C

2018-06-01

Oxidative stress is implicated in the pathogenesis of respiratory diseases, such as COPD and its comorbidities, asthma, idiopathic pulmonary fibrosis and radiation pneumonitis. Antioxidants drugs, such as small molecule thiols, nuclear erythroid-2 related factor 2 activators and catalytic enzyme mimetics have been developed to target oxidant-dependent mechanisms. The therapeutic effects of antioxidants have been generally disappointing. A small number of antioxidants are approved for clinical use, such as the small molecule thiol N-acetyl-l-cysteine for chronic obstructive pulmonary disease, and in the United States, the superoxide dismutase mimetic AEOL 10150 for severe radiation pneumonitis. The future use of antioxidants for the treatment of chronic respiratory diseases may require a precision medicine approach to identify responsive patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sensory evaluation of selected formulated milk barberry drinks using the fuzzy approach.

PubMed

Tahsiri, Zahra; Niakousari, Mehrdad; Khoshnoudi-Nia, Sara; Hosseini, Seyed Mohamad H

2017-05-01

Amid rigid competition in marketing to accomplish customers' needs, the cost of disappointment is too high. In an effort to escape market disappointment, one of the options to be considered is probing for customer satisfaction through sensory evaluation. This study aims to rank the six selected milk-barberry drink formulae out of 24 (code numbers S3, S4, S15, S16, S17 and S18) each having different milk:barberry:pectin amount (7: 3: 0.2; 6: 4: 0.2; 7: 3: 0.4, 6: 4: 0.4, 5: 5: 0.4 and 6: 4: 0.4), respectively, and to determine the best of quality attribute through sensory evaluation, using the fuzzy decision-making model. The selection was based on pH, total solid content, and degree of serum separation and rheological properties of the drinks. The results showed that the S4 had the highest acceptability, rated under the "very good" category, whereas the lowest acceptability was reported for the S3 which was classified under the "satisfactory" category. In summary, the ranking of the milk-barberry drinks was S4 > S17 > S16 > S15 > S18 > S3. Furthermore, quality attributes were ranked as taste > mouth feel > aroma > color. Results suggest that the fuzzy approach could be appropriately used to evaluate this type of sensory data.
Use of Emotional Cues for Lexical Learning: A Comparison of Autism Spectrum Disorder and Fragile X Syndrome

PubMed Central

Thurman, Angela John; McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi; Channell, Marie Moore; Mastergeorge, Ann; Abbeduto, Leonard

2014-01-01

The present study evaluated the ability of males with fragile X syndrome (FXS), nonsyndromic autism spectrum disorder (ASD), or typical development to learn new words by using as a cue to the intended referent an emotional reaction indicating a successful (excitement) or unsuccessful (disappointment) search for a novel object. Performance for all groups exceeded chance-levels in both search conditions. In the Successful Search condition, participants with nonsyndromic ASD performed similarly to participants with FXS after controlling for severity of ASD. In the Unsuccessful Search condition, participants with FXS performed significantly worse than participants with nonsyndromic ASD, after controlling for severity of ASD. Predictors of performance in both search conditions differed between the three groups. Theoretical and clinical implications are discussed. PMID:25318904
Obesity Pharmacotherapy: Current Perspectives and Future Directions

PubMed Central

Misra, Monika

2013-01-01

The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis PMID:23092275
Emergency contraception. Widely available and effective but disappointing as a public health intervention: a review

PubMed Central

Baird, D.T.; Cameron, S.; Evers, J.L.H.; Gemzell-Danielsson, K.; Glasier, A.; Moreau, C.; Trussell, J.; von Hertzen, H.; Crosignani, P.G.; La Vecchia, C.; Volpe, A.; Glasier, A.; Crosignani, P.G.

2015-01-01

Emergency contraception (EC) prevents pregnancy after unprotected sex or contraceptive failure. Use of EC has increased markedly in countries where a product is available over the counter, yet barriers to availability and use remain. Although effective in clinical trials, it has not yet been possible to show a public health benefit of EC in terms of reduction of unintended pregnancy rates. Selective progesterone receptor modulators developed as emergency contraceptives offer better effectiveness than levonorgestrel, but still EC is less effective than use of ongoing regular contraception. Methods which inhibit ovulation whenever they are taken or which act after ovulation to prevent implantation and strategies to increase the uptake of effective ongoing contraception after EC use would prevent more pregnancies. PMID:25678571
EFFECTS OF MEDICAL DISPUTES ON INTERNET COMMUNICATIONS OF NEGATIVE EMOTIONS AND NEGATIVE ONLINE WORD-OF-MOUTH.

PubMed

Lee, Yi-Chih; Wu, Wei-Li

2015-08-01

Emotions play an important role in human behavior. Negative emotions resulting from medical disputes are problems for medical personnel to solve but also have a significant impact on a hospital's reputation and people's trust in the hospital. One medical dispute case was chosen from an Internet news source to assess the correlation between people's negative emotions and negative online word-of-mouth. Convenience sampling was used in school faculties and university students who had shared their medical treatment experiences online were the research participants. A total of 221 Taiwanese participants volunteered (158 women, 63 men; ages: 26.7% under 19, 22.6% 20-29, 30.8% 30-39,19.9% over 40). Four negative emotions were measured using rating scales: uncertainty, anger, disappointment, and sadness. Four negative online word-of-mouth measures were: venting, advice search, helping receiver, and revenge. A modeled relationship was assessed by partial least square method (PLS). Then, people's positive emotions were further analyzed to assess changes after spreading negative word-of-mouth. The results showed that uncertainty had a positive effect on venting and advice search. People who felt anger or regret spread word-of-mouth in order to help the receiver. Disappointment may trigger the revenge behavior of negative word-of-mouth. Negative emotions could be relieved after engaging in the behavior of helping the receiver.
Bone Marrow Transplantation for Peripheral T-Cell Non-Hodgkins' Lymphoma in First Remission.

PubMed

Sharma, Manish; Pro, Barbara

2015-07-01

Opinion statement: Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases that carry, with the exception of anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma, a poor prognosis when treated with conventional chemotherapy. Historically, PTCL was treated like aggressive B-cell lymphomas, and to date cyclophosphamide, prednisone, vincristine, and doxorubicin (CHOP) remains the most commonly used regimen, despite disappointing results. Given the poor outcomes of PTCL patients, a number of studies have investigated the role of high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in the upfront setting, with different results. However, there are no prospective randomized trials, and the clinical benefit appears to be restricted to patients who achieve an objective response after induction chemotherapy. Nevertheless, with the exception of low-risk ALK+ anaplastic large cell lymphoma, in light of the available data, HDT/ASCT for consolidation should be recommended for patients deemed eligible. The results of phase II trials showed that allogeneic stem cell transplantation can cure some relapsed/refractory patients, and few studies have evaluated this strategy in the frontline setting. With the availability of recently approved new drugs as well as new targeted agents under investigation, a number of ongoing studies are testing novel combinations aiming to improve rate and durability of responses to induction chemotherapy.
Trueness verification of actual creatinine assays in the European market demonstrates a disappointing variability that needs substantial improvement. An international study in the framework of the EC4 creatinine standardization working group.

PubMed

Delanghe, Joris R; Cobbaert, Christa; Galteau, Marie-Madeleine; Harmoinen, Aimo; Jansen, Rob; Kruse, Rolf; Laitinen, Päivi; Thienpont, Linda M; Wuyts, Birgitte; Weykamp, Cas; Panteghini, Mauro

2008-01-01

The European In Vitro Diagnostics (IVD) directive requires traceability to reference methods and materials of analytes. It is a task of the profession to verify the trueness of results and IVD compatibility. The results of a trueness verification study by the European Communities Confederation of Clinical Chemistry (EC4) working group on creatinine standardization are described, in which 189 European laboratories analyzed serum creatinine in a commutable serum-based material, using analytical systems from seven companies. Values were targeted using isotope dilution gas chromatography/mass spectrometry. Results were tested on their compliance to a set of three criteria: trueness, i.e., no significant bias relative to the target value, between-laboratory variation and within-laboratory variation relative to the maximum allowable error. For the lower and intermediate level, values differed significantly from the target value in the Jaffe and the dry chemistry methods. At the high level, dry chemistry yielded higher results. Between-laboratory coefficients of variation ranged from 4.37% to 8.74%. Total error budget was mainly consumed by the bias. Non-compensated Jaffe methods largely exceeded the total error budget. Best results were obtained for the enzymatic method. The dry chemistry method consumed a large part of its error budget due to calibration bias. Despite the European IVD directive and the growing needs for creatinine standardization, an unacceptable inter-laboratory variation was observed, which was mainly due to calibration differences. The calibration variation has major clinical consequences, in particular in pediatrics, where reference ranges for serum and plasma creatinine are low, and in the estimation of glomerular filtration rate.
Long-Term Stress Management.

ERIC Educational Resources Information Center

Noel, James L.

1987-01-01

Techniques enabling faculty to decrease stress to more reasonable and productive levels are discussed, including management of chemical stressors, physical activities, relaxation, coping strategies for disappointment, emotional support, assertiveness, and time management. (MSE)
Clinical providers' experiences with returning results from genomic sequencing: an interview study.

PubMed

Wynn, Julia; Lewis, Katie; Amendola, Laura M; Bernhardt, Barbara A; Biswas, Sawona; Joshi, Manasi; McMullen, Carmit; Scollon, Sarah

2018-05-08

Current medical practice includes the application of genomic sequencing (GS) in clinical and research settings. Despite expanded use of this technology, the process of disclosure of genomic results to patients and research participants has not been thoroughly examined and there are no established best practices. We conducted semi-structured interviews with 21 genetic and non-genetic clinicians returning results of GS as part of the NIH funded Clinical Sequencing Exploratory Research (CSER) Consortium projects. Interviews focused on the logistics of sessions, participant/patient reactions and factors influencing them, how the sessions changed with experience, and resources and training recommended to return genomic results. The length of preparation and disclosure sessions varied depending on the type and number of results and their implications. Internal and external databases, online resources and result review meetings were used to prepare. Respondents reported that participants' reactions were variable and ranged from enthusiasm and relief to confusion and disappointment. Factors influencing reactions were types of results, expectations and health status. A recurrent challenge was managing inflated expectations about GS. Other challenges included returning multiple, unanticipated and/or uncertain results and navigating a rare diagnosis. Methods to address these challenges included traditional genetic counseling techniques and modifying practice over time in order to provide anticipatory guidance and modulate expectations. Respondents made recommendations to improve access to genomic resources and genetic referrals to prepare future providers as the uptake of GS increases in both genetic and non-genetic settings. These findings indicate that returning genomic results is similar to return of results in traditional genetic testing but is magnified by the additional complexity and potential uncertainty of the results. Managing patient expectations, initially identified in studies of informed consent, remains an ongoing challenge and highlights the need to address this issue throughout the testing process. The results of this study will help to guide future providers in the disclosure of genomic results and highlight educational needs and resources necessary to prepare providers. Future research on the patient experience, understanding and follow-up of recommendations is needed to more fully understand the disclosure process.
Soft Tissue Tumours: Their Natural History and Treatment

PubMed Central

Cade, Stanford

1951-01-01

A series of 153 patients, the largest yet recorded from a single source, suffering from soft tissue sarcoma is discussed. References to the literature show the rarity of such tumours, the vagueness of the nomenclature and the disappointing results of treatment. Of the 153 patients only 7 have no histological confirmation of the diagnosis. In 146, sections and histological reports are available. 148 patients have been followed up either to death or to date. ImagesFig. 1Fig. 2Fig. 3Fig. 4 PMID:14808223
Image analysis of the AXAF VETA-I x ray mirror

NASA Technical Reports Server (NTRS)

Freeman, Mark D.; Hughes, John P; Vanspeybroeck, L.; Weisskopf, M.; Bilbro, J.

1992-01-01

Initial core scan data of the VETA-I x-ray mirror proved disappointing, showing considerable unpredicted image structure and poor measured FWHM. 2-D core scans were performed, providing important insight into the nature of the distortion. Image deconvolutions using a ray traced model PSF was performed successfully to reinforce our conclusion regarding the origin of the astigmatism. A mechanical correction was made to the optical structure, and the mirror was tested successfully (FWHM 0.22 arcsec) as a result.
Treatment of small lower pole calculi--SWL vs. URS vs. PNL?

PubMed

Knoll, Thomas; Tasca, Andrea; Buchholz, Noor P

2011-03-01

According to current guideline recommendations extracorporeal shock wave lithotripsy (SWL) remains the first choice treatment for small and mid-sized renal calculi. However, the results of SWL treatment for lower pole stones can be disappointing whilst more invasive endoscopic modalities, such as flexible ureterorenoscopy (fURS) and percutaneous nephrolithotomy (PNL) are often considered more effective. This article summarizes a point-counterpoint discussion at the 9th eULIS symposium in Como, Italy, and discusses the potential advantages and disadvantages of the different therapeutic approaches.
Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease

PubMed Central

Orel, Rok; Kamhi Trop, Tina

2014-01-01

It has been presumed that aberrant immune response to intestinal microorganisms in genetically predisposed individuals may play a major role in the pathogenesis of the inflammatory bowel disease, and there is a good deal of evidence supporting this hypothesis. Commensal enteric bacteria probably play a central role in pathogenesis, providing continuous antigenic stimulation that causes chronic intestinal injury. A strong biologic rationale supports the use of probiotics and prebiotics for inflammatory bowel disease therapy. Many probiotic strains exhibit anti-inflammatory properties through their effects on different immune cells, pro-inflammatory cytokine secretion depression, and the induction of anti-inflammatory cytokines. There is very strong evidence supporting the use of multispecies probiotic VSL#3 for the prevention or recurrence of postoperative pouchitis in patients. For treatment of active ulcerative colitis, as well as for maintenance therapy, the clinical evidence of efficacy is strongest for VSL#3 and Escherichia coli Nissle 1917. Moreover, some prebiotics, such as germinated barley foodstuff, Psyllium or oligofructose-enriched inulin, might provide some benefit in patients with active ulcerative colitis or ulcerative colitis in remission. The results of clinical trials in the treatment of active Crohn’s disease or the maintenance of its remission with probiotics and prebiotics are disappointing and do not support their use in this disease. The only exception is weak evidence of advantageous use of Saccharomyces boulardii concomitantly with medical therapy in maintenance treatment. PMID:25206258
Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease.

PubMed

Orel, Rok; Kamhi Trop, Tina

2014-09-07

It has been presumed that aberrant immune response to intestinal microorganisms in genetically predisposed individuals may play a major role in the pathogenesis of the inflammatory bowel disease, and there is a good deal of evidence supporting this hypothesis. Commensal enteric bacteria probably play a central role in pathogenesis, providing continuous antigenic stimulation that causes chronic intestinal injury. A strong biologic rationale supports the use of probiotics and prebiotics for inflammatory bowel disease therapy. Many probiotic strains exhibit anti-inflammatory properties through their effects on different immune cells, pro-inflammatory cytokine secretion depression, and the induction of anti-inflammatory cytokines. There is very strong evidence supporting the use of multispecies probiotic VSL#3 for the prevention or recurrence of postoperative pouchitis in patients. For treatment of active ulcerative colitis, as well as for maintenance therapy, the clinical evidence of efficacy is strongest for VSL#3 and Escherichia coli Nissle 1917. Moreover, some prebiotics, such as germinated barley foodstuff, Psyllium or oligofructose-enriched inulin, might provide some benefit in patients with active ulcerative colitis or ulcerative colitis in remission. The results of clinical trials in the treatment of active Crohn's disease or the maintenance of its remission with probiotics and prebiotics are disappointing and do not support their use in this disease. The only exception is weak evidence of advantageous use of Saccharomyces boulardii concomitantly with medical therapy in maintenance treatment.
Approach towards an integrative drug treatment of Alzheimer's disease.

PubMed

Windisch, M

2000-01-01

At present pharmacotherapy of Alzheimer's disease (AD) is limited to acetylcholinesterase inhibitors. These drugs produce small, but consistent improvements of memory and global function, some are also positively influencing activities of daily living. This therapeutic approach neglects the complexity of AD and the fact that most of the degenerating neurons are not cholinergic. Acetylcholinesterase inhibitors are symptomatic drugs, with no influence on disease progression. There is a need for disease modifying compounds, or preventive drugs. Data are indicating that vitamin E has some ability to influence the disease progression. The potency of non-steroidal anti-inflammatory drugs (NSAIDs) or estrogen as preventive agents has to be explored further in prospective clinical studies. The initial hope in the use of naturally occurring neurotrophic factors, like nerve growth factor, to rescue cholinergic neurons from degeneration and to restore cognitive function has been disappointed in first, small clinical studies. The peptidergic drug Cerebrolysin exhibiting neurotrophic stimulation, neuroimmunotrophic regulation and induction of BBB glucose transporter expression, might be able to address the pathological changes of AD at different levels simultaneously. In addition to an impressive preclinical database, results from 3 placebo-controlled, double-blind studies demonstrate significant improvements of cognitive performance, global function and activities of daily living in AD patients. In all studies persisting improvements, up to 6 months after drug withdrawal, indicate a powerful disease modifying activity.
Effects of curcumin on HDL functionality.

PubMed

Ganjali, Shiva; Blesso, Christopher N; Banach, Maciej; Pirro, Matteo; Majeed, Muhammed; Sahebkar, Amirhossein

2017-05-01

Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function. Copyright © 2017 Elsevier Ltd. All rights reserved.
Cancer immunotherapy drives implementation science in oncology.

PubMed

Speiser, Daniel E; Flatz, Lukas

2014-01-01

Cancer immunotherapy has come a long way. The hope that immunological approaches may help cancer patients has sparked many initiatives in research and development (R&D). For many years, progress was modest and disappointments were frequent. Today, the increasing scientific and medical knowledge has established a solid basis for improvements. Considerable clinical success was first achieved for patients with hematological cancers. More recently, immunotherapy has entered center stage in the development of novel therapies against solid cancers. Together with R&D in angiogenesis, the field of immunology has fundamentally extended the scientific scope, which has evolved from a cancer-cell-centered view to a comprehensive and integrated vision of tumor biology. Current R&D is focused on a large array of possible disease mechanisms, driven by cancer cells, and amplified by tumor stroma, inflammatory and immunological actors, blood and lymph vessels, and the “macroenvironment," i.e. systemic mechanisms of the host, particularly of the haematopoietic system. Contrasting to this large spectrum of pathophysiological events promoting tumor growth, only a small number of biological mechanisms, namely of the immune system, have the potential to counteract tumor growth. They are of prime interest because therapeutic enhancement may result in clinical benefit for patients. This special issue is dedicated to immunotherapeutics against cancer, with particular emphasis on vaccination and combination therapies, providing updates and extended insight in this booming field.
Modulating PD-L1 expression in multiple myeloma: an alternative strategy to target the PD-1/PD-L1 pathway.

PubMed

Tremblay-LeMay, Rosemarie; Rastgoo, Nasrin; Chang, Hong

2018-03-27

Even with recent advances in therapy regimen, multiple myeloma patients commonly develop drug resistance and relapse. The relevance of targeting the PD-1/PD-L1 axis has been demonstrated in pre-clinical models. Monotherapy with PD-1 inhibitors produced disappointing results, but combinations with other drugs used in the treatment of multiple myeloma seemed promising, and clinical trials are ongoing. However, there have recently been concerns about the safety of PD-1 and PD-L1 inhibitors combined with immunomodulators in the treatment of multiple myeloma, and several trials have been suspended. There is therefore a need for alternative combinations of drugs or different approaches to target this pathway. Protein expression of PD-L1 on cancer cells, including in multiple myeloma, has been associated with intrinsic aggressive features independent of immune evasion mechanisms, thereby providing a rationale for the adoption of new strategies directly targeting PD-L1 protein expression. Drugs modulating the transcriptional and post-transcriptional regulation of PD-L1 could represent new therapeutic strategies for the treatment of multiple myeloma, help potentiate the action of other drugs or be combined to PD-1/PD-L1 inhibitors in order to avoid the potentially problematic combination with immunomodulators. This review will focus on the pathophysiology of PD-L1 expression in multiple myeloma and drugs that have been shown to modulate this expression.
Educational Success and Surrounding Culture

ERIC Educational Resources Information Center

Walters, Garrison

2016-01-01

The curriculum, instruction, and services we provide in schools, colleges, and universities matter a lot, but if we continue to ignore our students' "surrounding culture," progress toward a more educated nation will continue to be disappointing.
Disappointment and regret enhance corrugator reactivity in a gambling task

PubMed Central

Wu, Yin; Clark, Luke

2015-01-01

This study investigated how the corrugator and zygomaticus respond to decision outcomes (i.e., gains and losses). We used a gambling task in which participants were presented with obtained followed by non-obtained outcomes. Activity at the corrugator site was sensitive to decision outcomes, such that higher obtained losses (disappointment) and higher non-obtained gains (regret) both heightened corrugator reactivity. Activity at the zygomaticus site was not responsive to obtained or non-obtained outcomes, but did show sensitivity to emotional images in the same participants, in the form of a positive linear relationship with self-reported emotional valence. Corrugator activity was negatively related to emotional valence. The findings indicate the sensitivity of corrugator to objective decision outcomes and also counterfactual comparisons, highlighting the utility of facial electromyography in research on decision making and gambling behavior. PMID:25345723

Cough: an unmet clinical need

PubMed Central

Dicpinigaitis, Peter V

2011-01-01

Cough is among the most common complaints for which patients worldwide seek medical attention. Thus, the evaluation and treatment of cough result in tremendous financial expenditure and consumption of health care resources. Yet, despite the clinical significance of cough, research efforts aimed at improving diagnostic capabilities and developing more effective therapeutic agents have been, to date, disappointing in their limited scope and outcomes. Acute cough due to the common cold represents the most common type of cough. Currently, available medications for the symptomatic management of acute cough are inadequate due to lack of proven efficacy and/or their association with undesirable or intolerable side effects at anti-tussive doses. Subacute cough, often representing a prolonged post-viral response, is typically refractory to standard anti-tussive therapy. Few clinical trials have evaluated therapeutic options for subacute cough. Diagnostic challenges facing the clinician in the management of chronic cough include the determination of whether symptoms of upper airway cough syndrome (formerly, postnasal drip syndrome) or gastro-oesophageal reflux disease are indeed the underlying cause of cough. Chronic, refractory unexplained (formerly, idiopathic) cough must be distinguished from cough that has not been fully evaluated and treated according to current guideline recommendations. Eagerly awaited are new safe and effective anti-tussive agents for use when cough suppression is desired, regardless of underlying aetiology of cough, as well as practical, validated ambulatory cough counters to aid clinical assessment and future research in the field of cough. LINKED ARTICLES This article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 PMID:21198555
On Reproductive Work in Spain: Transnational Adoption, Egg Donation, Surrogacy.

PubMed

Marre, Diana; San Román, Beatriz; Guerra, Diana

2018-01-01

Spain's plummeting fertility since the late twentieth century may seem to reflect a waning desire for children. Nevertheless, reproductive disappointments resulting from gender inequalities cause many Spanish women to postpone motherhood and experience age-related fertility problems. For them, creating a family often becomes possible only through the reproductive labor of other women. Our analysis of transnational adoption, egg donation, and surrogacy in Spain shows how anonymity and altruism play out in these three strategies, with implications for the valuation of women's reproductive work and relationships among reproductive providers, intermediaries, recipients, and the resulting children.
Umami Increases Consumer Acceptability, and Perception of Sensory and Emotional Benefits without Compromising Health Benefit Perception.

PubMed

Miyaki, Takashi; Retiveau-Krogmann, Annlyse; Byrnes, Erin; Takehana, Shunji

2016-02-01

This study was undertaken to understand how consumers in the United States perceive umami-rich products, specifically low sodium chicken noodle soup. Results suggest that the addition of monosodium l-glutamate (MSG) at a concentration of 0.1% to 0.5%, alone or in synergy with 5'-ribonucleotides of inosine monophosphate (IMP) at 0.1% not only increases consumer acceptance but also positively impacts other aspects of consumer perception. Regardless of concentration of MSG and IMP, samples enhanced in umami compounds were perceived as more savory, flavorful, and less bland while providing a more homemade, fresh, and healthy wholesome taste than a control sample. From a functional and emotional benefit standpoint, when consuming umami-rich samples, consumers reported feeling significantly higher general satisfaction (they felt more content, relaxed, satisfied, less disappointed, dissatisfied…) and heightened positive emotions (happy, excited, indulgent…) than under the control condition. The feeling of being healthy while consuming the dish was not compromised. Last, when asked how they would feel if serving the soup sample to their family or friends, consumers projected feeling more positively under the umami-rich conditions (more happy, competent, loving, less dissatisfied or disappointed) compared to the control condition. © 2015 Institute of Food Technologists®
The role of an NHS library service in the UK: the perceptions of clinical managers in Portsmouth, UK.

PubMed

Blagden, Pauline

2007-06-01

Portsmouth NHS Library Service is exploring methods of raising its profile within its host organization and wishes to demonstrate its contribution to achieving organizational goals, perhaps by means of an impact study. The objective of this small scale study, regarded as a possible precursor to an impact study, was to identify areas where there is potential to increase awareness among clinical managers of the Library's contribution. An e-mail survey was sent to clinical managers to elicit their opinions regarding the contribution of the Library Service to organizational goals. Perhaps unsurprisingly, the role of the Library Service in education, research and effectiveness was most widely recognized. Of responses, 30/42 (71%) rated it as 'very important' and a further 11 (26%) rated it as 'important'. The low appreciation of the Library Service to Clinical Services is a disappointment in view of the body of research evidence. Only 12 respondents (29%) thought that the Library Service contributed 'significantly' by 'supporting informed and timely clinical decision making'. The study suggested areas where there might be scope to raise awareness of the Library contribution. In considering how best to achieve this, the benefits need to be weighed against the resource implications. Portsmouth NHS Library Service decided to increase its marketing efforts but not to carry out an impact study in the short term.
Health and safety executive inspection of U.K. semiconductor manufacturers.

PubMed

Watterson, Andrew; LaDou, Joseph

2003-01-01

Europe plays a major role in the international semiconductor industry, but has conducted few studies of the occupational health of its workers. An exception is in the United Kingdom, where, in two small studies, the Health and Safety Executive (HSE) evaluated some health effects of semiconductor work. Neither of these studies, largely restricted to Scotland, produced definitive results, and both were misused by industry to assert that they demonstrated no adverse health effect on workers. The results of the studies prompted semiconductor industry inspections recently completed by the HSE that included chip manufacturers in Scotland and other U.K. areas. The results of these inspections are disappointing.
New insights into amblyopia: binocular therapy and noninvasive brain stimulation.

PubMed

Hess, Robert F; Thompson, Benjamin

2013-02-01

The current approach to the treatment of amblyopia is problematic for a number of reasons. First, it promotes recovery of monocular vision but because it is not designed to promote binocularity, its binocular outcomes often are disappointing. Second, compliance is poor and variable. Third, the effectiveness of the treatment is thought to decrease with increasing age. We discuss 2 new approaches aimed at recovering visual function in adults with amblyopia. The first is a binocular approach to amblyopia treatment that is showing promise in initial clinical studies. The second is still in development and involves the use of well-established noninvasive brain stimulation techniques to temporarily alter the balance of excitation and inhibition in the visual cortex. Copyright © 2013 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.
Proteomics in pharmaceutical research and development.

PubMed

Cutler, Paul; Voshol, Hans

2015-08-01

In the 20 years since its inception, the evolution of proteomics in pharmaceutical industry has mirrored the developments within academia and indeed other industries. From initial enthusiasm and subsequent disappointment in global protein expression profiling, pharma research saw the biggest impact when relating to more focused approaches, such as those exploring the interaction between proteins and drugs. Nowadays, proteomics technologies have been integrated in many areas of pharmaceutical R&D, ranging from the analysis of therapeutic proteins to the monitoring of clinical trials. Here, we review the development of proteomics in the drug discovery process, placing it in a historical context as well as reviewing the current status in light of the contributions to this special issue, which reflect some of the diverse demands of the drug and biomarker pipelines. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Adaptive pathway development for Fabry disease: a clinical approach.

PubMed

Schuller, Yvonne; Arends, Maarten; Körver, Simon; Langeveld, Mirjam; Hollak, Carla E M

2018-06-01

Fabry disease (FD) is a rare X-chromosome-linked lysosomal storage disorder. Although initial expectations of enzyme replacement therapy (ERT) were high, it is now clear that real-world effectiveness is disappointing and evidence gathering has been inadequate. In retrospect, development of ERT for FD had several shortcomings. Little convincing evidence on the effectiveness existed at time of authorization. Also, post-marketing evaluation failed to generate sufficient and relevant data for adequate evaluation on effectiveness. Adaptive pathways might have benefitted ERT development by: (i) involving healthcare professionals, patients, health technology assessment bodies and payers in the development process; (ii) iterative development, starting with initial authorization in classical males; (iii) a clear real-world data collection plan; (iv) an independent disease registry; and (v) prescription control. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
Overview of gene therapy clinical progress including cancer treatment with gene-modified T cells

PubMed Central

Brenner, Malcolm K.; Okur, Fatma V.

2010-01-01

It is now twenty years since the first legal gene transfer studies were approved, and there has been considerable disappointment in the slow rate of progress that followed the initial studies. Gradually, however, as the limitations of available vectors are acknowledged and overcome, and with advances in our understanding of the molecular and cell biology of genetic diseases and of cancer, unequivocal successes are now being reported. In this paper we describe the remaining major roadblocks to successful gene therapy and outline approaches to overcome them. We also illustrate how genetically modified immune system cells are already being used for the effective treatment of hematological and other malignancies, and how these approaches are being modified so that they can be effective in treating a broader range of malignancies. PMID:20008253
Irreversibility of advanced osteoporosis: Limited role for pharmacologic intervention

NASA Technical Reports Server (NTRS)

Parfitt, A. M.

1994-01-01

Osteoporosis is of medical interest only because it increases bone fragility and risk of fracture, and except for relief of symptoms, preventing fracture is the only purpose of intervention. To prevent the first fracture, adequate bone density must be accumulated and conserved, but to prevent subsequent fracture, bone density must be augmented so that the supportive function of the skeleton can be restored. Almost 50 years after the recognition of post menopausal osteoporosis as a clinical entity, not one of the many treatments that have been used has been demonstrated to be efficacious in reducing subsequent fracture risk. My purpose is not to recite this chronicle of disappointment, but to account for it in terms of bone biology, to consider some possible exceptions, and to reiterate the importance of preventing damage to the skeleton rather than belatedly attempting its repair.
Advances in the management of dyslipidemia.

PubMed

Kampangkaew, June; Pickett, Stephen; Nambi, Vijay

2017-07-01

Cardiovascular disease is the leading cause of morbidity and mortality in the United States and therapies aimed at lipid modification are important for the reduction of cardiovascular risk. There have been many exciting advances in lipid management over the recent years. This review discusses these recent advances as well as the direction of future studies. Several recent clinical trials support low-density lipoprotein cholesterol (LDL-c) reduction beyond maximal statin therapy for improved cardiovascular outcomes. Ezetimibe reduced LDL-c beyond maximal statin therapy and was associated with improved cardiovascular outcomes for high-risk populations. Further LDL-c reduction may also be achieved with proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibition and a recent trial, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), was the first to show reduction in cardiovascular events for evolocumab. Additional outcome studies of monoclonal antibody and RNA-targeted PCSK9 inhibitors are underway. Quantitative high-density lipoprotein cholesterol (HDL-c) improvements have failed to have clinical impact to date; most recently, cholesteryl ester transfer protein inhibitors and apolipoprotein infusions have demonstrated disappointing results. There are still ongoing trials in both of these areas, but some newer therapies are focusing on HDL functionality and not just the absolute HDL-c levels. There are several ongoing studies in triglyceride reduction including fatty acid therapy, inhibition of apolipoprotein C-3 or ANGTPL3 and peroxisome proliferator-activated receptor-α agonists. Lipid management continues to evolve and these advances have the potential to change clinical practice in the coming years.
Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract--a pilot study.

PubMed

Kacerovská, Denisa; Pizinger, Karel; Majer, Filip; Smíd, Frantisek

2008-01-01

Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.
Research to Encourage Exercise for Fibromyalgia (REEF): Use of Motivational Interviewing Design and Method

PubMed Central

Ang, Dennis C.; Kaleth, Anthony S.; Bigatti, Silvia; Mazzuca, Steve; Saha, Chandan; Hilligoss, Janna; Lengerich, Mimi; Bandy, Robert

2010-01-01

Fibromyalgia (FM), defined as the presence of both chronic widespread pain and the finding of 11/18 tender points on examination, is an illness associated with major personal and societal burden. Supervised aerobic exercise is an important treatment modality to improve patient symptoms. Unfortunately, adherence to an exercise regimen after a structured supervised program is disappointingly low. Since FM is a chronic illness, studies are needed to test strategies that would enhance exercise adherence in these individuals. Individuals who are able to adhere to exercise almost always maintain the symptomatic benefits of exercise. The objective of this paper was to describe the protocol of the Research to Encourage Exercise for Fibromyalgia (REEF). REEF is a randomized attention-controlled trial that seeks to test the efficacy of 6 sessions of telephone delivered motivational interviewing (MI) that targets exercise adherence to improve FM-relevant clinical outcomes (i.e., physical function and pain severity). The trial has recently completed enrolling 216 subjects, and randomization has resulted in well balanced groups. Details on the study design, MI program, and treatment fidelity are provided in the paper. Outcome assessments at week 12, week 24 and week 36 will test the immediate, intermediate and long term effects of exercise-based MI on adherence (as measured by the Community Health Activities Model Program for Seniors/CHAMPS and accelerometer) and clinical outcomes. When completed, REEF will determine whether exercise-based MI could be utilized as a management strategy to sustain the clinical benefits of exercise for FM. PMID:20828634
Research to Encourage Exercise for Fibromyalgia (REEF): use of motivational interviewing design and method.

PubMed

Ang, Dennis C; Kaleth, Anthony S; Bigatti, Silvia; Mazzuca, Steve; Saha, Chandan; Hilligoss, Janna; Lengerich, Mimi; Bandy, Robert

2011-01-01

Fibromyalgia (FM), defined as the presence of both chronic widespread pain and the finding of 11/18 tender points on examination, is an illness associated with major personal and societal burden. Supervised aerobic exercise is an important treatment modality to improve patient symptoms. Unfortunately, adherence to an exercise regimen after a structured supervised program is disappointingly low. Since FM is a chronic illness, studies are needed to test strategies that would enhance exercise adherence in these individuals. Individuals who are able to adhere to exercise almost always maintain the symptomatic benefits of exercise. The objective of this paper was to describe the protocol of the Research to Encourage Exercise for Fibromyalgia (REEF). REEF is a randomized attention-controlled trial that seeks to test the efficacy of 6 sessions of telephone delivered motivational interviewing (MI) that targets exercise adherence to improve FM-relevant clinical outcomes (i.e., physical function and pain severity). The trial has recently completed enrolling 216 subjects, and randomization has resulted in well-balanced groups. Details on the study design, MI program, and treatment fidelity are provided in the paper. Outcome assessments at week 12, week 24 and week 36 will test the immediate, intermediate and long-term effects of exercise-based MI on adherence (as measured by the Community Health Activities Model Program for Seniors/CHAMPS and accelerometer) and clinical outcomes. When completed, REEF will determine whether exercise-based MI could be utilized as a management strategy to sustain the clinical benefits of exercise for FM. Copyright © 2010 Elsevier Inc. All rights reserved.
Citicoline for acute ischemic stroke in Mexican hospitals: a retrospective postmarketing analysis.

PubMed

Leon-Jimenez, C; Chiquete, E; Cantu, C; Miramontes-Saldana, M J; Andrade-Ramos, M A; Ruiz-Sandoval, J L

2010-06-01

Some neuroprotective agents have shown benefits in animal models, but disappointing results in humans. Citicoline is used in several countries as coadjuvant treatment in acute ischemic stroke (AIS) patients; however, there are no retrospective postmarketing surveillances on the experience of citicoline in Mexico. The aim of this study was to evaluate the correlation between citicoline exposure and functional outcome at discharge and at 30 and 90 days post-stroke, in a retrospective case-control design on systematic descriptive databases from three referral hospitals. Clinical records of 173 consecutively registered patients were analyzed, 86 of whom were treated with citicoline within the first 48 h after AIS and the remaining 87 were untreated, randomly selected controls matched for age (+/- 5 years), gender and NIHSS (+/- 1 point) at hospital admission. Pretreatment conditions were similar between groups. Compared with controls, exposure to citicoline was associated with a significantly lower 30-day mean and median modified Rankin score (in both, P < 0.05). After paired multivariate analyses (controlled for NIHSS, age, gender, hospital arrival in < 24 h, thrombolysis and comorbidities) citicoline was independently associated with a lower 90-day mortality risk (P = 0.047) and with fewer in-hospital complications (mainly infections and sepsis, P = 0.001). In this observational study, citicoline use was associated with a better functional status and lower rates of short-term mortality, possibly due to fewer in-hospital systemic complications. The putative benefits should be interpreted as clinical associations, since this is not a randomized, controlled clinical trial. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.
Is belief larger than fact: expectations, optimism and reality for translational stem cell research

PubMed Central

2012-01-01

Background Stem cell (SC) therapies hold remarkable promise for many diseases, but there is a significant gulf between public expectations and the reality of progress toward clinical application. Public expectations are fueled by stakeholder arguments for research and public funding, coupled with intense media coverage in an ethically charged arena. We examine media representations in light of the expanding global landscape of SC clinical trials, asking what patients may realistically expect by way of timelines for the therapeutic and curative potential of regenerative medicine? Methods We built 2 international datasets: (1) 3,404 clinical trials (CT) containing 'stem cell*' from ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Search Portal; and (2) 13,249 newspaper articles on SC therapies using Factiva.com. We compared word frequencies between the CT descriptions and full-text newspaper articles for the number containing terms for SC type and diseases/conditions. We also developed inclusion and exclusion criteria to identify novel SC CTs, mainly regenerative medicine applications. Results Newspaper articles focused on human embryonic SCs and neurological conditions with significant coverage as well of cardiovascular disease and diabetes. In contrast, CTs used primarily hematopoietic SCs, with an increase in CTs using mesenchymal SCs since 2007. The latter dominated our novel classification for CTs, most of which are in phases I and II. From the perspective of the public, expecting therapies for neurological conditions, there is limited activity in what may be considered novel applications of SC therapies. Conclusions Given the research, regulatory, and commercialization hurdles to the clinical translation of SC research, it seems likely that patients and political supporters will become disappointed and disillusioned. In this environment, proponents need to make a concerted effort to temper claims. Even though the field is highly promising, it lacks significant private investment and is largely reliant on public support, requiring a more honest acknowledgement of the expected therapeutic benefits and the timelines to achieving them. PMID:23131007
The Difficulty in Finding Relationships Between ERPs and Clinical Symptoms of Schizophrenia.

PubMed

Ford, Judith M

2018-01-01

It has been surprisingly difficult to find associations between neural signatures of schizophrenia and the symptoms that define it. That is, many of the legacy components of the event-related potential (ERP)- P50, N100, P200, P300-are reduced in patients with schizophrenia, in first-degree relatives of patients with schizophrenia, in schizophrenia patients early in their illness, and even in people at clinical high risk for schizophrenia. Nevertheless, these ERP components tend to be relatively insensitive to symptoms. This might be due to a number of reasons. First, this could reflect a lack of relationship, a failure to report disappointing findings, or a failure to test for relationships. Second, many ERP studies were not designed to be sensitive to symptoms or to the mechanisms that might underlie them. Third, assessing symptoms is sometimes dependent on the patients' ability to describe unfathomable experiences and the clinicians' ability to understand and interpret them. Fourth, medications and comorbidities may decouple the symptoms from the neurobiology. Finally, we must also consider the possibility that the schizophrenia diagnosis breeds truer than the symptoms it comprises.
CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke

PubMed Central

Adibhatla, Rao Muralikrishna; Hatcher, J.F.; Tureyen, K.

2007-01-01

Cytidine-5′-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM1 ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM1 ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline. PMID:16153613
Correlations between commonly used clinical outcome scales and patient satisfaction after total knee arthroplasty.

PubMed

Kwon, Sae Kwang; Kang, Yeon Gwi; Kim, Sung Ju; Chang, Chong Bum; Seong, Sang Cheol; Kim, Tae Kyun

2010-10-01

Patient satisfaction is becoming increasingly important as a crucial outcome measure for total knee arthroplasty. We aimed to determine how well commonly used clinical outcome scales correlate with patient satisfaction after total knee arthroplasty. In particular, we sought to determine whether patient satisfaction correlates better with absolute postoperative scores or preoperative to 12-month postoperative changes. Patient satisfaction was evaluated using 4 grades (enthusiastic, satisfied, noncommittal, and disappointed) for 438 replaced knees that were followed for longer than 1 year. Outcomes scales used the American Knee Society, Western Ontario McMaster University Osteoarthritis Index scales, and Short Form-36 scores. Correlation analyses were performed to investigate the relation between patient satisfaction and the 2 different aspects of the outcome scales: postoperative scores evaluated at latest follow-ups and preoperative to postoperative changes. The Western Ontario McMaster University Osteoarthritis Index scales function score was most strongly correlated with satisfaction (correlation coefficient=0.45). Absolute postoperative scores were better correlated with satisfaction than the preoperative to postoperative changes for all scales. Level IV (retrospective case series). Copyright © 2010 Elsevier Inc. All rights reserved.
Civil society perspectives on negative biomedical HIV prevention trial results and implications for future trials.

PubMed

Essack, Zaynab; Koen, Jennifer; Slack, Catherine; Lindegger, Graham; Newman, Peter A

2012-01-01

Community engagement is crucial to ongoing development and testing of sorely needed new biomedical HIV prevention technologies. Yet, negative trial results raise significant challenges for community engagement in HIV prevention trials, including the early termination of the Cellulose Sulfate microbicide trial and two Phase IIb HIV vaccine trials (STEP and Phambili). The present study aimed to explore the perspectives and experiences of civil society organization (CSO) representatives regarding negative HIV prevention trial results and perceived implications for future trials. We conducted in-depth interviews with 14 respondents from a broad range of South African and international CSOs, and analyzed data using thematic analysis. CSO representatives reported disappointment in response to negative trial results, but acknowledged such outcomes as inherent to clinical research. Respondents indicated that in theory negative trial results seem likely to impact on willingness to participate in future trials, but that in practice people in South Africa have continued to volunteer. Negative trial results were described as having contributed to improving ethical standards, and to a re-evaluation of the scientific agenda. Such negative results were identified as potentially impacting on funding for trials and engagement activities. Our findings indicate that trial closures may be used constructively to support opportunities for reflection and renewed vigilance in strategies for stakeholder engagement, communicating trial outcomes, and building research literacy among communities; however, these strategies require sustained resources for community engagement and capacity-building.

Micronutrients, vitamins, and cancer risk.

PubMed

Schorah, C J

1999-01-01

There is now considerable evidence that a high intake of fruit and vegetables can decrease the risk of developing cancer. While it is by no means clear how this particular diet alters cancer risk, there is substantial metabolic and experimental evidence to implicate antioxidant micronutrients, The dietary components include some vitamins, such as C and E, the carotenoids, and the flavinoids. In chemical systems, cell culture, and experimental animals, these components have the ability to quench the carcinogenic potential of reactive oxygen species and other carcinogens, such as N-nitrosocompounds. Some of these micronutrients can act synergistically, and high concentrations are often found in tissues, such as the leucocytes and mucosal cells, that are particularly prone to reactive species attack. Experimental systems containing these micronutrients also appear to be able to reduce DNA damage and mutagenesis. However, assessment of individual vitamin intake, as opposed to fruit and vegetable consumption, does not increase the protective association of these components, and the results of intervention studies in man, especially with carotenoids, have been disappointing. We await the results of other clinical trials, but as yet, there is insufficient evidence to recommend supplements of these particular micronutrients for the prevention of cancer. However, it would be prudent to suggest changes in diet that would increase consumption of fruit and vegetables, such as a diet is clearly associated with protection.
Graft-versus-lymphoma effect in refractory cutaneous T-cell lymphoma after reduced-intensity HLA-matched sibling allogeneic stem cell transplantation.

PubMed

Herbert, K E; Spencer, A; Grigg, A; Ryan, G; McCormack, C; Prince, H M

2004-09-01

Cutaneous T-cell lymphomas (CTCL) are rare diseases that, in their advanced stages or in transformation, have a poor prognosis. Autologous stem cell transplantation (Au-SCT) after high-dose therapy has yielded disappointing results. Allogeneic transplantation (allo-SCT) provides the potential advantage of an immune-mediated graft-versus-lymphoma (GVL) effect. Reduced-intensity allo-SCT potentially offers a GVL effect, but with diminished toxicity related to the induction regimen; however, published experience with this approach in CTCL is limited. We report a series of three patients (age 35-49) with advanced, refractory (n=2) or transformed (n=1) CTCL who underwent reduced-intensity allo-SCT in the context of active disease. All three survived the peri-transplant period and, despite later having disease relapse, all exhibited evidence of a GVL effect. Relapses of the disease were in the context of immune suppression for graft-versus-host disease (GVHD), and when immune suppression was reduced, responses were regained. A comparison is made of these results to those in a review of the published literature to date. We conclude that while a GVL can be achieved for CTCL with reduced-intensity allogeneic transplantation, the clinical benefits are short lived and novel approaches are required to obtain sustained remissions.
[Pathologic childhood aerophagia].

PubMed

Delaperrière, N; Orega, M; Maurage, C; Faure, N; Labarthe, F; Roullet-Renoleau, N; Leddet, I; Robert, M; Rolland, J-C

2007-01-01

"Air swallowing" described as being part of functional gastrointestinal disorders in "Rome criteria" in 1999 is often misdiagnosed, particularly in non-mentally deficient children. To recognize "air swallowing" child and to describe any progress according to the treatment. This retrospective study reports 13 cases of children without mental deficiency or neuromuscular disease. Clinical elements and precise histories are detailed and we have contacted consulting doctors or families for news. Ten boys and 3 girls, from 2,5 years to 10 years old, were referred for long lasting pain or abdominal distension. Numerous laboratory investigations were always normal. Diagnosis relied upon the observation of air swallowing and X-Rays views of gastric distension. Air swallowing was observed 7 times, 9 children had twitches and 3 language troubles. In 10 cases, X-rays showed gastric and colic distension. Three children have Chilaïditi syndrome. Favourable results followed in 12 cases after an average of 28 months of treatment. One case was lost for follow-up. Treatment was long, often disappointing and required the intervention of a psychiatrist, a paediatrician and (temporarily) a speech therapist. Pathological childhood aerophagia is often underdiagnosed and deserves to be better known by paediatricians, psychiatrists and surgeons. A late diagnosis leads to many negative results and causes anxiety. An early diagnosis should lead to a multidisciplinary care.
Disappointing mid-term results after laparoscopic gastric banding in young patients.

PubMed

Lanthaler, Monika; Sieb, Michael; Strasser, Stefan; Weiss, Helmut; Aigner, Franz; Nehoda, Hermann

2009-01-01

When gastric banding was introduced as a bariatric operation about 12 years previously, its early results were promising, with a low complication rate. Only a few long-term studies on this subject have been published. This study was performed to assess our results with laparoscopic gastric banding in young patients after
Positive psychotherapy for smoking cessation enhanced with text messaging: Protocol for a randomized controlled trial.

PubMed

Kahler, Christopher W; Surace, Anthony; Rebecca, E F; Gordon, B A; Cioe, Patricia A; Spillane, Nichea S; Parks, Acacia; Bock, Beth C; Brown, Richard A

2018-06-21

Despite reductions in cigarette smoking in the U.S., improvements in the efficacy of smoking cessation treatments are needed, as rates of sustained abstinence remain disappointingly low. Both low positive affect and high negative affect contribute to smoking relapse and constitute viable targets for smoking cessation interventions. Although some clinical trials have evaluated interventions to address depression as a smoking relapse risk factor, very few have focused on positive affect. Recently, we developed and conducted a preliminary clinical trial of a smoking cessation treatment that targets positive affect and cognitions by incorporating interventions rooted in positive psychology. The current randomized controlled trial will expand upon this preliminary trial to test whether this positive psychology-informed approach results in higher smoking cessation rates compared to a time-matched standard smoking cessation treatment control. Three hundred and forty adult daily smokers will be randomly assigned to either positive psychotherapy for smoking cessation or standard behavioral smoking cessation counseling. Participants will meet weekly with a study counselor for 6 weeks and will receive transdermal nicotine patch and text messaging smoking cessation support. Additionally, text messaging in the positive psychotherapy condition will encourage engagement in positive psychology-specific strategies for boosting mood and staying smoke free. Smoking cessation outcomes will be measured at 12, 26, and 52 weeks following target quit date. Results from this study will provide evidence on whether incorporating positive psychology interventions into smoking cessation treatment can improve smoking cessation outcomes relative to standard behavioral counseling with nicotine patch and text messaging. Copyright © 2018. Published by Elsevier Inc.
Refeeding syndrome: screening, incidence, and treatment during parenteral nutrition.

PubMed

Walmsley, Russell S

2013-12-01

The possible deleterious effects of feeding after a period of prolonged starvation have been known for over 60 years. The resultant biochemical disturbance, symptoms, and signs have been termed the refeeding syndrome (RS). The key to the pathophysiology is the stimulation of insulin release resulting in anabolic activity. Depleted electrolyte and micronutrient stores are overwhelmed and cellular function disrupted. A concise definition of RS is not agreed and hampers interpretation of clinical data. Hypophosphatemia and appearance of tissue edema/pathological fluid shifts are the most often agreed diagnostic criteria. The characteristics of particular patient groups at risk have been recognized for some time, and there are guidelines from the National Institute for Clinical Excellence in the UK to aid recognition of individuals at high risk along with protocols for initiating nutrition. Using loose diagnostic criteria, RS appears to occur in 4% of cases of parenteral nutrition (PN) when case records were reviewed by experts in a large study into PN care in the UK. Disappointingly, prescribers recognized only 50% of at risk cases. Early data from a similar study in New Zealand appear to show a similar pattern. Prospective series looking at patients receiving nutrition support in institutions with Nutrition Support Teams have found an incidence of 1-5%. RS is still underrecognized. Patients receiving PN should be counted as being in a high-risk category and feeding protocols to avoid RS applied. Low rates of RS then occur and death from this cause be avoided. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
A New Program in pain medicine for medical students: Integrating core curriculum knowledge with emotional and reflective development

PubMed Central

Murinson, Beth B.; Nenortas, Elizabeth; Mayer, R. Sam; Mezei, Lina; Kozachik, Sharon; Nesbit, Suzanne; Haythornthwaite, Jennifer A.; Campbell, James N.

2010-01-01

Objective Improvements in clinical pain care have not matched advances in scientific knowledge, and innovations in medical education are needed. Several streams of evidence indicate that pain education needs to address both the affective and cognitive dimensions of pain. Our aim was to design and deliver a new course in pain establishing foundation-level knowledge while comprehensively addressing the emotional development needs in this area. Setting 118 first year medical students at Johns Hopkins School of Medicine. Outcome measures Performance was measured by multiple choice tests of pain knowledge, attendance, reflective pain portfolios and satisfaction measures. Results Domains of competence in pain knowledge included central and peripheral pain signaling, pharmacological management of pain with standard analgesic medications, neuromodulating agents and opioids; cancer pain, musculoskeletal pain, nociceptive, inflammatory, neuropathic, geriatric, and pediatric pain. Socio-emotional development (portfolio) work focused on increasing awareness of pain affect in self and others and enhancing the commitment to excellence in pain care. Reflections included observations on a brief pain experience (cold pressor test), the multi-dimensionality of pain, the role of empathy and compassion in medical care, the positive characteristics of pain-care role models, the complex feelings engendered by pain and addiction including frustration and disappointment, and aspirations and commitments in clinical medicine. The students completing feedback expressed high levels of interest in pain medicine as a result of the course. Discussion We conclude that a four-day pain course incorporating sessions with pain- specialists, pain medicine knowledge, and design-built elements to strengthen emotional skills is an effective educational approach. PMID:21276187
Generality and cultural variation in the experience of regret.

PubMed

Breugelmans, Seger M; Zeelenberg, Marcel; Gilovich, Thomas; Huang, Wen-Hsien; Shani, Yaniv

2014-12-01

Regret is the prototypical decision-related emotion. Most theory and research on regret comes from the United States and Europe, but recent research has suggested potential cross-cultural differences in regret. We examined generality and cultural variation in the experience of regret. A cross-cultural study compared experiences of regret with those of disappointment and guilt as reported by participants from the United States (n = 143), the Netherlands (n = 147), Israel (n = 148), and Taiwan (n = 115). We found strong evidence for generality of the distinct emotion components of regret, compared with those of disappointment and guilt. We also found cultural variation in the frequency and intensity of regret in intrapersonal situations (regrets about outcomes affecting the self) and interpersonal regrets (regrets about outcomes affecting others). Whereas in the U.S. sample, regret was experienced more intensely in intrapersonal than interpersonal situations, both emotions were experienced more intensely in interpersonal situations in the Taiwanese sample.
Can Seeking Happiness Make People Happy? Paradoxical Effects of Valuing Happiness

PubMed Central

Mauss, Iris B.; Tamir, Maya; Anderson, Craig L.; Savino, Nicole S.

2011-01-01

Happiness is a key ingredient of well-being. It is thus reasonable to expect that valuing happiness will have beneficial outcomes. We argue that this may not always be the case. Instead, valuing happiness could be self-defeating because the more people value happiness, the more likely they will feel disappointed. This should apply particularly in positive situations, in which people have every reason to be happy. Two studies support this hypothesis. In Study 1, female participants who valued happiness more (vs. less) reported lower happiness when under conditions of low, but not high, life stress. In Study 2, compared to a control group, female participants who were experimentally induced to value happiness reacted less positively to a happy, but not a sad, emotion induction. This effect was mediated by participants’ disappointment at their own feelings. Paradoxically, therefore, valuing happiness may lead people to be less happy just when happiness is within reach. PMID:21517168
Neural Substrates of Counterfactual Emotions After Risky Decisions in Late Adolescents and Young Adults.

PubMed

Rodrigo, María José; Padrón, Iván; de Vega, Manuel; Ferstl, Evelyn

2018-03-01

Adolescents' neural substrates of emotional reactions to the consequences of risky decisions are poorly understood. In this functional magnetic resonance imaging study, 30 late adolescents and 30 young adults made risky and neutral decisions in social scenarios and received valenced outcomes. Negative outcomes in risky decisions eliciting regret, as compared with negative outcomes in neutral decisions eliciting disappointment, activated executive control (orbitofrontal cortex) and self-relevance regions (middle temporal gyrus [MTG], posterior cingulate cortex, and precuneus) for both age groups. Young adults showed more activation than adolescents in regret and disappointment as compared with relief and elation conditions in the avoidance (insula), action monitoring (inferior frontal gyrus, pre-SMA, and caudate), and social-cognition regions (superior temporal sulcus and MTG). These late socio-emotional developments may pave the way for more adaptive decision-making behavior in social contexts. © 2018 Society for Research on Adolescence.
Experiences of Nigerian Internationally Educated Nurses Transitioning to United States Health Care Settings.

PubMed

Iheduru-Anderson, Kechinyere C; Wahi, Monika M

2018-04-01

Successful transition to practice of internationally educated nurses (IENs) can critically affect quality of care. The aim of this study was to characterize the facilitators and barriers to transition of Nigerian IENs (NIENs) to the United States health care setting. Using a descriptive phenomenology approach, 6 NIENs were interviewed about their transitional experiences in the United States. Thematic methods were used for data analysis. The three major themes identified from the participants' stories were "fear/anger and disappointment" (FAD), "road/journey to success/overcoming challenges" (RJO), and "moving forward" (MF). The FAD theme predominated, including experiences of racism, bullying, and inequality. The RJO theme included resilience, and the MF theme encompassed personal growth. NIENs face personal and organizational barriers to adaptation, especially fear, anger and disappointment. Future research should seek to develop a model for optimal adaptation that focuses on improving both personal and organizational facilitators and decreasing barriers.
Disappointment and regret enhance corrugator reactivity in a gambling task.

PubMed

Wu, Yin; Clark, Luke

2015-04-01

This study investigated how the corrugator and zygomaticus respond to decision outcomes (i.e., gains and losses). We used a gambling task in which participants were presented with obtained followed by non-obtained outcomes. Activity at the corrugator site was sensitive to decision outcomes, such that higher obtained losses (disappointment) and higher non-obtained gains (regret) both heightened corrugator reactivity. Activity at the zygomaticus site was not responsive to obtained or non-obtained outcomes, but did show sensitivity to emotional images in the same participants, in the form of a positive linear relationship with self-reported emotional valence. Corrugator activity was negatively related to emotional valence. The findings indicate the sensitivity of corrugator to objective decision outcomes and also counterfactual comparisons, highlighting the utility of facial electromyography in research on decision making and gambling behavior. © 2014 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.
Treatment outcomes of a Numeric Rating Scale (NRS)-guided pharmacological pain management strategy in symptomatic knee and hip osteoarthritis in daily clinical practice.

PubMed

Snijders, Gijs F; van den Ende, Cornelia H M; van den Bemt, Bart J F; van Riel, Piet L C M; van den Hoogen, Frank H J; den Broeder, Alfons A

2012-01-01

To describe the results of a Numeric Rating Scale (NRS)-guided pharmacological pain management strategy in symptomatic knee and hip osteoarthritis (OA) in daily clinical practice. In this observational cohort study, standardised conservative treatment was offered to patients with symptomatic knee and/or hip OA referred to secondary care. Pain management was guided by a NRS for pain, aiming for NRS ≤4. The first step in pharmacological treatment was paracetamol (acetaminophen) in case of no recent use in adequate dose. In case of treatment failure, patients switched to a non-steroidal anti-inflammatory drug (NSAID) and eventually to a second NSAID, each after a 4-week trial period. Predictors for response to treatment were identified. Moreover, reasons for protocol violations were collected. Three-hundred and forty-seven patients were included. The proportion of patients that reached a response after paracetamol, first and second NSAID was 25% (59/234), 16% (31/190) and 11% (10/87), respectively. Non-adherence to protocol occurred in 46% of cases when switch of analgesic was advised, mainly due to unwillingness of patients to change the analgesic. Identified predictors for response to analgesics included higher age, lower patient global assessment, less stiffness and more radiographic severity. Adequate use of paracetamol and switching to a NSAID after failing paracetamol resulted in moderate treatment response percentages, whereas the result of a second NSAID was disappointing in patients with advanced knee and hip OA. Predictors for response included patient and disease related factors. A substantial part of patients with NRS >4 were unwilling to change their analgesics.
Comparison of metabolic pathways of different α-N-heterocyclic thiosemicarbazones.

PubMed

Pelivan, Karla; Frensemeier, Lisa M; Karst, Uwe; Koellensperger, Gunda; Heffeter, Petra; Keppler, Bernhard K; Kowol, Christian R

2018-03-01

Clinical failure of novel drugs is often related to their rapid metabolism and excretion. This highlights the importance of elucidation of their pharmacokinetic profile already at the preclinical stage of drug development. Triapine, the most prominent representative of α-N-heterocyclic thiosemicarbazones, was investigated in more than 30 clinical phase I/II trials, but the results against solid tumors were disappointing. Recent investigations from our group suggested that this is, at least partially, based on the fast metabolism and excretion. In order to establish more detailed structure/activity/metabolism relationships, herein a panel of 10 different Triapine derivatives was investigated for their metabolic pathways. From the biological point of view, the panel consists of terminally dimethylated thiosemicarbazones with nanomolar IC 50 values, derivatives with micromolar cytotoxicities comparable to Triapine and a completely inactive representative. To study the oxidative metabolism, a purely instrumental approach based on electrochemistry/mass spectrometry was applied and the results were compared to the data obtained from microsomal incubations. Overall, the investigated thiosemicarbazones underwent the phase I metabolic reactions dehydrogenation, hydroxylation, oxidative desulfuration (to semicarbazone and amidrazone) and demethylation. Notably, dehydrogenation resulted in a ring-closure reaction with formation of thiadiazoles. Although strong differences between the metabolic pathways of the different thiosemicarbazones were observed, they could not be directly correlated to their cytotoxicities. Finally, the metabolic pathways for the most cytotoxic compound were elucidated also in tissues collected from drug-treated mice, confirming the data obtained by electrochemical oxidation and microsomes. In addition, the in vivo experiments revealed a very fast metabolism and excretion of the compound. Graphical abstract Structure/activity/metabolisation relationships for 10 anticancer thiosemicarbazones were established using electrochemical oxidation coupled to mass spectrometry (EC-MS) and human liver microsomes analyzed by LC-MS.
Comparison of early exploration at Platanares (Honduras) and Wairakei (New Zealand)

USGS Publications Warehouse

Truesdell, A.H.; Glover, R.B.; Janik, C.J.; Brown, K.L.; Goff, F.

1989-01-01

Early exploration at Wairakei, New Zealand, is compared with the present state of exploration of Platanares, Honduras. In retrospect, geothermometer temperatures favor Platanares (e.g., 220 vs. 190??C for Na-K-Ca), but two 600-m drill holes encountered lower temperatures (160??C). Wairakei, explored before the advent of chemical geothermometry, also had disappointing early drilling results (but better than Platanares; one of the first six holes hit T > 180??C). The Wairakei drilling program was nevertheless continued at full speed and by well 20 a successful drilling strategy was discovered.
The therapy of Sjogren's syndrome: a review.

PubMed

Coaccioli, S; Giuliani, M; Puxeddu, A

2007-01-01

The Sjogren's syndrome (SS) is an chronic inflammatory autoimmune disease of the exocrine glands as well as of internal apparatus. The therapy of exocrinopathy is represented by parasympathomimetic drugs such as pilocarpine and cevimeline. The therapy of systemic manifestations, actually is represented by the inhibitors of TNF alfa, as well as leflunomide, methotrexate and cyclosporine-A, but the results are quite insufficient and disappointed. In order to the involvement of B-cell function in the pathogenesis of SS, one of the most important option in the future should be specific inhibitors of that cells.
[Visual development and amblyopia prophylaxis in pediatric glaucoma].

PubMed

Steffen, H

2011-07-01

In children with congenital glaucoma the functional long-term result is often disappointing even if the intraocular pressure is well controlled. The reason for this discrepancy is attributed to amblyogenic factors responsible for interfering with normal visual development. These amblyogenic factors are corneal edema, irregular astigmatism and non-corrected ametropia as monocular causes. Binocular causes are anisometropia-induced suppression and strabismus. Full ametropic correction and a very early prophylaxis and treatment of amblyopia with a close follow-up are mandatory to reduce amblyogenic visual impairment in children with congenital glaucoma.
Prevention of Youthful Marijuana Use.

PubMed

Cermak, Timmen L; Banys, Peter

2016-01-01

Considerable money and effort have been expended in attempts to prevent drug use by youth, with disappointing results. Too often, prevention programs have singled out youth with simplistic messages of exaggerated risk and the same politically acceptable solution for all-abstinence. Historically, prevention efforts have been less effective by not being soundly based in science and failing also to address adult drug and alcohol use as part of the problem. The Institute of Medicine continuum of care model developed in 1994 offers a framework for a more sophisticated, three-tiered approach to prevention, defined as all services provided prior to a clinical diagnosis of a substance use disorder. By dividing prevention efforts into universal (delivered to broad populations without consideration of individual risk for developing substance use disorder), selected (targeting sub-groups of individuals identified on the basis of characteristics known to create an elevated risk for substance use disorder), and indicated (addressing individuals identified on the basis of manifest risk behaviors), prevention can be better tailored to meet different levels of need. Student Assistance Programs (SAPs) and community coalitions provide examples of how IOM's continuum of care model can be integrated into drug prevention programs for youth.
[Residual risk: The roles of triglycerides and high density lipoproteins].

PubMed

Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

2016-06-01

In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.
The effect of RAAS blockade on the progression of diabetic nephropathy.

PubMed

Roscioni, Sara S; Heerspink, Hiddo J Lambers; de Zeeuw, Dick

2014-02-01

The renin-angiotensin-aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy.

Risk factors and prevention of vascular complications in polycythemia vera.

PubMed

Barbui, T; Finazzi, G

1997-01-01

Risk factors for vascular complications in polycythemia vera (PV) include laboratory and clinical findings. Among laboratory values, the hematocrit has been clearly associated with thrombosis, particularly in the cerebral circulation. Platelet count is a possible but not yet clearly established predictor of vascular complications. Platelet function tests are of little help in prognostic evaluation because most attempts to correlate these abnormalities with clinical events have been disappointing. Clinical predictors of thrombosis include increasing age and a previous history of vascular events. Identifying risk factors for thrombosis is important to initiate therapy. Phlebotomy is associated with an increased incidence of thrombosis in the first 3 to 5 years, whereas chemotherapy may induce a higher risk of secondary malignancies after 7 to 10 years of follow-up. New cytoreductive drugs virtually devoid of mutagenic risk include interferon-alpha and anagrelide, but their role in reducing thrombotic complications remains to be demonstrated. Antithrombotic drugs, such as aspirin, are frequently used in PV, despite doubts regarding safety and efficacy. Two recent studies from the Gruppo Italiano Studio Policitemia Vera (GISP) assessed the rate of major thrombosis as well as the tolerability of low-dose aspirin in PV patients. These investigations created a favorable scenario for launching a European collaborative clinical trial (ECLAP study) aimed at testing the efficacy of low-dose aspirin in preventing thrombosis and prolonging survival in patients with PV.
Emergency contraception. Widely available and effective but disappointing as a public health intervention: a review.

PubMed

2015-04-01

Emergency contraception (EC) prevents pregnancy after unprotected sex or contraceptive failure. Use of EC has increased markedly in countries where a product is available over the counter, yet barriers to availability and use remain. Although effective in clinical trials, it has not yet been possible to show a public health benefit of EC in terms of reduction of unintended pregnancy rates. Selective progesterone receptor modulators developed as emergency contraceptives offer better effectiveness than levonorgestrel, but still EC is less effective than use of ongoing regular contraception. Methods which inhibit ovulation whenever they are taken or which act after ovulation to prevent implantation and strategies to increase the uptake of effective ongoing contraception after EC use would prevent more pregnancies. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain.

PubMed

Komirishetty, Prashanth; Areti, Aparna; Gogoi, Ranadeep; Sistla, Ramakrishna; Kumar, Ashutosh

2016-10-01

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.
Immunotherapy of elderly acute myeloid leukemia: light at the end of a long tunnel?

PubMed

Rafelson, William M; Reagan, John L; Fast, Loren D; Lim, Seah H

2017-11-01

Although it is possible to induce remission in the majority of the patients with acute myeloid leukemia (AML), many patients still die due to disease relapse. Immunotherapy is an attractive option. It is more specific. The memory T cells induced by immunotherapy may also provide the long-term tumor immunosurveillance to prevent disease relapse. Although immunotherapy of AML started in the early 1970s, its clinical impact has been disappointing. Recent advances in tumor immunology and immunotherapeutic agents have rekindled interest. Here, we provide a review of the history of AML immunotherapy, discuss why AML is well suited for immunotherapeutic approaches and present the biological obstacles that affect the success of immunotherapy. Finally, we put forward a new paradigm of AML immunotherapy that utilizes a combination of immunotherapeutic agents sequentially to enhance the in vivo tumor immunogenicity and effective priming and propagation of tumor-specific cytotoxic T cells.
Learning from the U.S. Department of Veterans Affairs Quality Enhancement Research Initiative: QUERI Series

PubMed Central

Graham, Ian D; Tetroe, Jacqueline

2009-01-01

As the recent collection of papers from the Quality Enhancement Research Initiative (QUERI) Series indicates, knowledge is leading to considerable action in the United States (U.S.) Department of Veterans Affairs (VA). The QUERI Series offers clinical researchers, implementation scientists, health systems, and health research funders from around the globe a unique window into the both the practice and science of implementation or knowledge translation (KT) in the VA. By describing successes and challenges as well as setbacks and disappointments, the QUERI Series is all the more useful. From the vantage point of Canadian KT researchers and officials at a national health research funding agency, we offer a number of observations and lessons that can be learned from QUERI. "Knowledge, if it does not determine action, is dead to us." Plotinus (Roman philosopher 205AD-270AD) PMID:19267920
[Dr. Henry Wigderson--the first neurosurgeon in Eretz-Israel].

PubMed

Feinsod, Moshe

2006-07-01

The vision of Hadassah Medical Organization and the Hebrew University in Jerusalem was to establish a University Hospital where clinical excellence and high academic level will be the hallmark of its departments. More than seventy years ago, guided by this spirit, the leaders of the two institutions attempted to establish a department of neurosurgery, which, at the time in only a few countries, was making its initial steps as an independent discipline. It was only during World War II that Hadassah could bring over a specialist in neurosurgery who worked for nearly three years in the Hadassah Hospital on Mount Scopus. This article describes the way Dr. Henry Wigderson was selected to be the first neurosurgeon in Eretz-Israel, his activities and the incorporation of the idea, in spite of the disappointment caused by his departure, that even at times of distress, neurosurgery is not a luxury but an indispensable part of an forward-looking medical institution.
Electronic Records, Registries, and the Development of "Big Data": Crowd-Sourcing Quality toward Knowledge.

PubMed

Dewdney, Summer B; Lachance, Jason

2016-01-01

Despite many perceived advances in treatment over the past few decades, cancer continues to present a significant health burden, particularly to the aging US population. Forces including shrinking funding mechanisms, cost and quality concerns, as well as disappointing clinical outcomes have driven a surge of recent efforts into utilizing the technological innovation that has permeated other industries by leveraging large and complex data sets, so called "big data." In this review, we will review some of the history of oncology data collection, including the earliest data registries, as well as explore the future directions of this new brand of research while highlighting some of the more recent and promising efforts to harness the power of the electronic health record and the multitude of data co-located there, in an effort to improve individualized cancer-related outcomes in rapid real time.
Time and timelessness: inscription and representation.

PubMed

Levine, Howard B

2009-04-01

Time is a real dimension of the physical universe and a subjective matter of mind. Depending on their relationship to Eros and the Death Instinct, our feelings about time and timelessness may serve disparate ends- positive or negative, constructive or destructive. The conflicts that emerge between time and timelessness will be affected by and drawn into our conflicts between the reality principle and the pleasure principle and by our capacity to acknowledge and bear the losses, hurts, and disappointments with which life presents us and the hopes and possibilities that life may hold. The "making" and inscribing of time-i.e., articulating and ordering mental elements in the act of representation, symbolization, and verbal linkage of previously unrepresented and inchoate proto-mental elements and states-are central to psychic functioning and the psychoanalytic process. Clinical material will illustrate these processes and their relation to the binding and mastery of trauma: internal and external, massive and cumulative.
Orlistat. No hurry....

PubMed Central

1999-01-01

Treatments for obesity are disappointing. None has yet shown an effect on morbidity and mortality. Nondrug treatments are poorly assessed. Stable long-term weight loss necessitates long-term management. Orlistat (Xenical, Hoffman-La Roche), a gastrointestinal lipase inhibitor, is indicated, in combination with a low-calorie diet, for management of obesity. The assessment file is bulky and methodologically sound, at least in terms of the weight loss end point. During medium-term trials (12 to 24 months), orlistat administered at a dose of 120 mg three times daily and combined with dietary intervention had a moderate positive effect on body weight (-3.5 kg on average). No longer-term trials have been done. It is unknown whether this drug affects morbidity and mortality linked to obesity. In clinical trials, patients treated with orlistat had an increased frequency of breast cancer. This potential risk is currently being assessed in a specific trial. Gastrointestinal adverse effects are frequent. Treatment is costly. PMID:10540693
Cancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment.

PubMed

Polireddy, Kishore; Chen, Qi

2016-01-01

Pancreatic cancer is one of the most lethal cancers among all malignances, with a median overall survival of <1 year and a 5-year survival of ~5%. The dismal survival rate and prognosis are likely due to lack of early diagnosis, fulminant disease course, high metastasis rate, and disappointing treatment outcome. Pancreatic cancers harbor a variety of genetic alternations that render it difficult to treat even with targeted therapy. Recent studies revealed that pancreatic cancers are highly enriched with a cancer stem cell (CSC) population, which is resistant to chemotherapeutic drugs, and therefore escapes chemotherapy and promotes tumor recurrence. Cancer cell epithelial to mesenchymal transition (EMT) is highly associated with metastasis, generation of CSCs, and treatment resistance in pancreatic cancer. Reviewed here are the molecular biology of pancreatic cancer, the major signaling pathways regulating pancreatic cancer EMT and CSCs, and the advancement in current clinical and experimental treatments for pancreatic cancer.
Error, contradiction and reversal in science and medicine.

PubMed

Coccheri, Sergio

2017-06-01

Error and contradictions are not "per se" detrimental in science and medicine. Going back to the history of philosophy, Sir Francis Bacon stated that "truth emerges more readily from error than from confusion", and recently Popper introduced the concept of an approximate temporary truth that constitutes the engine of scientific progress. In biomedical research and in clinical practice we assisted during the last decades to many overturnings or reversals of concepts and practices. This phenomenon may discourage patients from accepting ordinary medical care and may favour the choice of alternative medicine. The media often enhance the disappointment for these discrepancies. In this note I recommend to transfer to patients the concept of a confirmed and dependable knowledge at the present time. However, physicians should tolerate uncertainty and accept the idea that medical concepts and applications are subjected to continuous progression, change and displacement. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Recent advances in microparticle and nanoparticle delivery vehicles for mucosal vaccination.

PubMed

McNeela, E A; Lavelle, E C

2012-01-01

The great potential of mucosal vaccination is widely accepted but progress in the clinical development of subunit mucosal vaccines has been disappointing. Of the available approaches, the use of polymer-based microparticles is attractive because these delivery vehicles can be specifically tailored for vaccines and they offer the potential for integration of adjuvant. Here we address recent developments in the use of particulates as mucosal vaccines and the potential of novel targeting strategies, formulation approaches and adjuvant combinations to enhance the efficacy of particle-based mucosal vaccines. This review discusses the current status of mucosal vaccines based on particles and highlights several of the strategies that are currently under investigation for improving their immunogenicity. These include enhancing the stability of formulations in the luminal environment, increasing uptake by specifically targeting particles to mucosal inductive sites, and augmenting immunogenicity through co-formulation with immunostimulatory agents.
[Schnitzler's syndrome].

PubMed

Henry, B; Néel, A; Barbarot, S; Masseau, A; Hamidou, M

2013-04-01

Schnitzler syndrome (SS) is a rare clinical entity, which belongs to the spectrum of monoclonal gammapathy-associated systemic disorders. Its pathophysiology remains elusive, even if it is tempting to consider it as a late onset and probably acquired auto-inflammatory syndrome. SS mainly occurs in the fifth and sixth decade, and present with an urticariform rash with periodic fever and/or osteoarticular pain. Systemic inflammation and monoclonal gammapathy (overwhelmingly IgM kappa) are constant features. SS is a chronic disease, which can severely impair quality of life of the affected individuals. Many drugs have been used and proved disappointing. In the last few years, accumulating reports provided evidence for the dramatic efficacy of anakinra, which has revolutionized the management of most severe cases. The main long-term threat to these patients is to develop a lymphoproliferative disorder (mainly Waldenström's macroglobulinemia). The mechanisms underlying the different facets of the disease remain to be elucidated. Copyright © 2013. Published by Elsevier SAS.
Marital crises in oncology patients. An approach to initial intervention by primary clinicians.

PubMed

Peteet, J; Greenberg, B

1995-05-01

Life-threatening illnesses such as cancer may precipitate marital crises in vulnerable relationships, and oncology clinicians often feel uncertain about how to approach them. This paper presents a framework for initial intervention based on the nature of the principal threat to the relationship. Immature relationships need distance and support for their identity as a couple; hostile dependent couples need to find consensus in order to structure communication; physically abusive relationships require monitoring in order to promote safety; and estranged couples need help in understanding their disappointment and identifying available support. Clinicians working in oncology can help couples in crisis by promoting a realistic balance of independence and dependence, clarifying the complexity of factors contributing to the crisis, considering referral for couples treatment, communicating with the team while respecting patients' confidences, and by choosing clear and compatible clinical roles. Primary clinicians can stabilize and treat marital crises, but need access to medically knowledgeable couples' therapists.
Initiatives to improve feedback culture in the final year of a veterinary program.

PubMed

Warman, Sheena M; Laws, Emma J; Crowther, Emma; Baillie, Sarah

2014-01-01

Despite the recognized importance of feedback in education, student satisfaction with the feedback process in medical and veterinary programs is often disappointing. We undertook various initiatives to try to improve the feedback culture in the final clinical year of the veterinary program at the University of Bristol, focusing on formative verbal feedback. The initiatives included E-mailed guidelines to staff and students, a faculty development workshop, and a reflective portfolio task for students. Following these initiatives, staff and students were surveyed regarding their perceptions of formative feedback in clinical rotations, and focus groups were held to further explore issues. The amount of feedback appeared to have increased, along with improved recognition of feedback by students and increased staff confidence and competence in the process. Other themes that emerged included inconsistencies in feedback among staff and between rotations; difficulties with giving verbal feedback to students, particularly when it relates to professionalism; the consequences of feedback for both staff and students; changes and challenges in students' feedback-seeking behavior; and the difficulties in providing accurate, personal end-of-rotation assessments. This project has helped improve the feedback culture within our clinics; the importance of sustaining and further developing the feedback culture is discussed in this article.
Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome.

PubMed

Sproule, Douglas M; Kaufmann, Petra

2008-10-01

Since the initial description almost 25 years ago, the syndrome of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) has been a useful model to study the complex interplay of factors that define mitochondrial disease. This syndrome, most commonly caused by an A-to-G transition mutation at position 3243 of the mitochondrial genome, is typified by characteristic neurological manifestations including seizures, encephalopathy, and strokelike episodes, as well as other frequent secondary manifestations including short stature, cognitive impairment, migraines, depression, cardiomyopathy, cardiac conduction defects, and diabetes mellitus. In this review, we discuss the history, pathogenesis, clinical features, and diagnostic and management strategies of mitochondrial disease in general and of MELAS in particular. We explore features of mitochondrial genetics, including the concepts of heteroplasmy, mitotic segregation, and threshold effect, as a basis for understanding the variability and complicated inheritance patterns seen with this group of diseases. We also describe systemic manifestations of MELAS-associated mutations, including cardiac, renal, endocrine, gastrointestinal, and endothelial abnormalities and pathology, as well as the hypothetical role of derangements to COX enzymatic function in driving the unique pathology and clinical manifestations of MELAS. Although therapeutic options for MELAS and other mitochondrial diseases remain limited, and recent trials have been disappointing, we also consider current and potential therapeutic modalities.
Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) "cachexia-anorexia in chronic wasting diseases" and "nutrition in geriatrics".

PubMed

Muscaritoli, M; Anker, S D; Argilés, J; Aversa, Z; Bauer, J M; Biolo, G; Boirie, Y; Bosaeus, I; Cederholm, T; Costelli, P; Fearon, K C; Laviano, A; Maggio, M; Rossi Fanelli, F; Schneider, S M; Schols, A; Sieber, C C

2010-04-01

Chronic diseases as well as aging are frequently associated with deterioration of nutritional status, loss muscle mass and function (i.e. sarcopenia), impaired quality of life and increased risk for morbidity and mortality. Although simple and effective tools for the accurate screening, diagnosis and treatment of malnutrition have been developed during the recent years, its prevalence still remains disappointingly high and its impact on morbidity, mortality and quality of life clinically significant. Based on these premises, the Special Interest Group (SIG) on cachexia-anorexia in chronic wasting diseases was created within ESPEN with the aim of developing and spreading the knowledge on the basic and clinical aspects of cachexia and anorexia as well as of increasing the awareness of cachexia among health professionals and care givers. The definition, the assessment and the staging of cachexia, were identified as a priority by the SIG. This consensus paper reports the definition of cachexia, pre-cachexia and sarcopenia as well as the criteria for the differentiation between cachexia and other conditions associated with sarcopenia, which have been developed in cooperation with the ESPEN SIG on nutrition in geriatrics. Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Writing a Condolence Note

MedlinePlus

... into the scheme of things. “It’s part of God’s plan.” What plan? God planned to have a little girl fall down ... is already feeling some anger and disappointment toward God. “Call if you need anything.” It becomes obvious ...
Homeschooling Comes of Age.

ERIC Educational Resources Information Center

Lines, Patricia M.

2000-01-01

The rapidly growing homeschooling movement has been around for centuries. No definitive data exist on the scope of homeschooling, but limited data note that homeschooling families are generally religious, conservative, middle income, educated whites. People often consider homeschooling after disappointments with public school quality. Homeschooled…
Do parents excuse the misbehavior of children with physical or emotional symptoms? An investigation of the pediatric sick role.

PubMed

Walker, L S; Garber, J; Van Slyke, D A

1995-06-01

Assessed attributions and responses to descriptions of the misbehavior of children with symptoms of physical and emotional illnesses. Subjects (160 mothers; 160 fathers) read a vignette about a child in one of four illness conditions (medically explained pain with organic etiology; medically unexplained pain, depression, well) who was described as misbehaving at home and school. Within each illness condition, the child protagonist varied by age (8 vs. 16) and gender. A between-subjects design was used in which subjects made judgments regarding causes and responsibility for the child's misbehavior, affective reactions to the child, and the consequences that should be administered to the child. Results indicated that, in comparison to subjects' perceptions of the misbehavior of children in the other conditions, subjects viewed the misbehavior of children with medically explained pain as less intentional, more excusable, and due to causes that were less internal to the child. Subjects held children with medically explained pain less responsible for their misbehavior and indicated that they would respond to them with less anger, disappointment, blame, and punishment than to children in the other conditions. Subjects did not hold children with symptoms of depression and children with unexplained pain complaints less responsible for their misbehavior, but indicated that they would respond to them with less anger, disappointment, and punishment than to well children.

Immune checkpoint inhibitors for non-small-cell lung cancer: does that represent a 'new frontier'?

PubMed

Pilotto, Sara; Kinspergher, Stefania; Peretti, Umberto; Calio, Anna; Carbognin, Luisa; Ferrara, Roberto; Brunelli, Matteo; Chilosi, Marco; Tortora, Giampaolo; Bria, Emilio

2015-01-01

Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.
Human gene therapy: a brief overview of the genetic revolution.

PubMed

Misra, Sanjukta

2013-02-01

Advances in biotechnology have brought gene therapy to the forefront of medical research. The prelude to successful gene therapy i.e. the efficient transfer and expression of a variety of human gene into target cells has already been accomplished in several systems. Safe methods have been devised to do this, using several viral and no-viral vectors. Two main approaches emerged: in vivo modification and ex vivo modification. Retrovirus, adenovirus, adeno-associated virus are suitable for gene therapeutic approaches which are based on permanent expression of the therapeutic gene. Non-viral vectors are far less efficient than viral vectors, but they have advantages due to their low immunogenicity and their large capacity for therapeutic DNA. To improve the function of non-viral vectors, the addition of viral functions such as receptor mediated uptake and nuclear translocation of DNA may finally lead to the development of an artificial virus. Gene transfer protocols have been approved for human use in inherited diseases, cancers and acquired disorders. In 1990, the first successful clinical trial of gene therapy was initiated for adenosine deaminase deficiency. Since then, the number of clinical protocols initiated worldwide has increased exponentially. Although preliminary results of these trials are somewhat disappointing, but human gene therapy dreams of treating diseases by replacing or supplementing the product of defective or introducing novel therapeutic genes. So definitely human gene therapy is an effective addition to the arsenal of approaches to many human therapies in the 21st century.
Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer

PubMed Central

Raeeszadeh‐Sarmazdeh, Maryam; Radisky, Derek C.

2017-01-01

ABSTRACT Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell‐associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re‐evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial–mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold. J. Cell. Biochem. 118: 3531–3548, 2017. © 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. PMID:28585723
[Toe transplantation in congenital malformations of the hand].

PubMed

Foucher, G

1997-11-01

Toe transfer is a well established procedure for thumb and finger reconstruction after mutilation. The indications in congenital malformations are a mater of controversy. Out of a personal series of 209 patients, 42 were children presenting a congenital malformation. Thirty six, with 46 transfers were available for review. There is only one failure at the beginning of our experience. The main indication was absence of pinch either due to absence of thumb (like in congenital band syndrome or some extreme cases of ulnar club hand or cleft hand) or absence of long finger (like in symbrachydactyly monodactylous type) or lack of both thumb and finger (like in peromelic type of symbrachydactyly). In this last type, we have been disappointed by the functional result of the distal implantation of two second toes taken from both feet; we have proposed a "stub" operation consisting in a second toe transfer on the anterior aspect of the radial epiphysis to take advantage of the mobility of the wrist and the availability of plenty tendon transfer (in this proximal situation). When planing to "built" an absent pincer, an early age is mandatory for operation (mean 12 months), to ensure a good cortical integration. A less frequent indication is a partial toe transfer with a vascularized epiphysis to provide growth and mobility in some cases of thumb hypoplasia (like in symbrachydactyly or Blauth and Manske type III b). Results are difficult to assess due to the early operation but if the mobility has been disappointing (mean 32 degrees), sensibility (mean 2PD 5 mm) and growth were excellent.
Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.

PubMed

Guan, Jikui; Fransson, Susanne; Siaw, Joachim Tetteh T; Treis, Diana; Van den Eynden, Jimmy; Chand, Damini; Umapathy, Ganesh; Svenberg, Petter; Ruuth, Kristina; Wessman, Sandra; Shamikh, Alia; Jacobsson, Hans; Gordon, Lena; Stenman, Jakob; Larsson, Erik; Svensson, Par-Johan; Hansson, Magnus; Martinsson, Tommy; Kogner, Per; Palmer, Ruth H; Hallberg, Bengt

2018-06-15

Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma. Cold Spring Harbor Laboratory Press.
Contemporary clinical trials in ventricular tachycardia and fibrillation: implications of ESVEM, CASCADE, and CASH for clinical management.

PubMed

Anderson, J L

1995-10-01

Recent clinical trials in patients with ventricular tachycardia (VT) or fibrillation (VF) have occurred in the setting of the disappointing results of postinfarction secondary prevention studies using Class I antiarrhythmics (e.g., CAST). ESVEM addressed in a randomized trial whether electrophysiologic study (EPS) or Holter monitoring (HM) is a more accurate predictor of long-term antiarrhythmic drug efficacy in VT/VF patients (N=486) and what the relative efficacy of various antiarrhythmic agents is for VT/VF. Surprisingly, arrhythmia recurrence rates were not significantly different by the method of determining an efficacy prediction. However, arrhythmia recurrence and mortality were lower (by about 50% at 1 year) in patients treated with sotalol (a mixed Class II/III agent) than with other drugs (Class I). CASCADE evaluated empiric amiodarone versus guided (EPS or HM) standard (Class I) therapy in survivors of out-of-hospital cardiac arrest due to VF. The primary endpoint of cardiac death, resuscitated VF, or syncopal shock (in ICD patients) was reduced by amiodarone compared with conventional therapy (9% vs 23% at 1 year). An interim report of the ongoing CASH study suggested in 230 survivors of cardiac arrest that propafenone (Class IC) provided less effective prophylaxis (approximately 20% 1-year mortality) compared with randomly assigned therapies with amiodarone, metoprolol, or an ICD (approximately 14% mortality rates) and was excluded from further study. These studies have led to a paradigm shift in the approach to antiarrhythmic therapy of VT/VF: drugs with antisympathetic plus Class III (refractoriness prolonging) action (i.e., sotalol, amiodarone) are superior to traditional drugs with Class I( conduction slowing) effects, even when guided by EPS or HM.
76 FR 23839 - United States

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-28

... a significant form of competition to attract digital animation employees and other employees covered... the digital animation industry. Finally, while Mr. Martin is of the view that others may be involved... the proposed settlement. After reading the proposed settlement I was rather disappointed. If I may...
Best Magazines of 2006

ERIC Educational Resources Information Center

Couch, Clayton A.

2007-01-01

Deeming 2006 disappointing for the magazine industry may be an exaggeration. Nevertheless, publishers have undoubtedly seen better years. Advertising revenue declined for a number of popular print titles, with publications such as "Field & Stream," "Outdoor Life," "Vanity Fair," "The New Yorker," "Skiing," and "Jane" shedding significant numbers…
"EJ" in Focus: Webs of Support for Learning to Teach English Together

ERIC Educational Resources Information Center

McCann, Thomas M.

2013-01-01

the critical episodes that inevitably face any teacher. These episodes include the challenge to manage a daunting workload while following habits necessary to stay healthy; to recover from disappointments, errors, and disrespect; to form positive relationships with students,…
Courtside: Celebration

ERIC Educational Resources Information Center

Zirkel, Perry A.

2005-01-01

In this era of educational choice, school accountability, research-based practices, and commercial competition--illustrated by but not exclusive to No Child Left Behind--some schools, public and private, make claims that resemble false advertising and that some parents rely on, to their disappointment and even detriment. Moreover, the laudable…
The Quality Education Challenge.

ERIC Educational Resources Information Center

Downey, Carolyn J.; And Others

Attempts to implement W. Edwards Deming's Total Quality Management (TQM) principles in education and transform school systems into world-class, quality learning environments have proved somewhat disappointing. This book asserts that educators need a way to translate the ideas about corporate quality for adaptation and use in schools. The…
Natural Partners: Resource-Based and Integrative Learning.

ERIC Educational Resources Information Center

Porter, John R.

1992-01-01

With resource-based learning projects, college students at the Philadelphia College of Pharmacy and Science develop a better sense of the information resources available, the nature of scientific literature, and the characteristics of scientific writing. Faculty motivations, benefits, and disappointments with this approach are addressed.…
Affective Consequences of Teachers' Psychological Investment.

ERIC Educational Resources Information Center

Stephenson, Don

1990-01-01

Relationships between teachers' (N=740) psychological condition (burned-out, worn-out, or healthy) and their affective reactions to student success or failure were examined. Findings indicated that affects of anger, guilt, pride, and disappointment varied with and could be predicted from knowledge of teachers' psychological conditions. (IAH)
Stop misbehaving!

PubMed

Neill, Ushma S

2006-07-01

Scientists are usually thought to be beyond reproach, but with the recent spate of high-profile ethical transgressions by scientists, the public's trust in science and scientists is deteriorating. The numerous cases of scientific misconduct that have crossed my desk in the last year leave me disenchanted, disappointed, and disillusioned.
Closure of a human tissue biobank: individual, institutional, and field expectations during cycles of promise and disappointment

PubMed Central

Stephens, Neil; Dimond, Rebecca

2015-01-01

Biobanks are increasingly being established to act as mediators between patient-donors and researchers. In practice, some of these will close. This paper details the experiences of one such bank. We report interviews with the bank's staff and oversight group during the period when the bank ceased biobanking activity, reconfigured as a disseminator of best practice, before then closing altogether. The paper makes three distinct contributions: (i) to provide a detailed account of the establishment, operational challenges, and eventual closure of the bank, which makes clear the rapid turnover in a cycle of promise and disappointment; (ii) to explore this in terms of a novel analytical focus upon field, institutional, and individual expectations; and (iii) to use this typology to demonstrate how, even after the bank's closure, aspects of its work were reconfigured and reused in new contexts. This provides a unique empirical analysis of the under-reported issue of biobank closure. PMID:26740793
Treatment of chronic Achilles tendon rupture by shortening suture and free sural triceps aponeurosis graft.

PubMed

Khiami, F; Di Schino, M; Sariali, E; Cao, D; Rolland, E; Catonné, Y

2013-09-01

The Bosworth technique is old but still widely used. It involves problems of precisely determining the length of the Achilles tendon and of a volume effect in the turndown area. A new reconstruction technique is assessed, based on free sural triceps aponeurosis transfer without turndown, associated to tendon shortening suture. Twenty-three patients were assessed by AOFAS score and clinical examination (plus MRI in 14 cases) at a mean 24.5 months' follow-up. Mean age was 52.1 years. Mean pre-operative AOFAS score was 63.6/100. Mean postoperative AOFAS score was 96.1. Mean graft length was 7.5 cm. Surgical revision was required for one case of postoperative infection. Twelve patients resumed leisure sports at their previous level by a mean 9.4 ± 2 months; three competitive sportsmen resumed sport at their previous level by a mean 7.6 months. None were dissatisfied or disappointed with their operation. MRI performed at 1 year found increased tendon volume without abnormality in 57% of cases; 43% showed abnormal images. Functional results were comparable to literature reports. It can be difficult to determine Achilles length for the Bosworth technique: this is made easier by conserving a fibrous support of a length determined with reference to the healthy side. The technique avoids aponeurosis turndown, and thus avoids the problem of plasty volume effect. The two cases of cutaneous complication occurred in the two most elderly patients, raising the question of the indications for reconstructive surgery in the elderly. The abnormalities found on MRI concerned scar tissue remodeling in patients with good or excellent clinical results. Level IV, retrospective study. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
Vitrification: an effective new approach to oocyte banking and preserving fertility in cancer patients.

PubMed

Cobo, A; Domingo, J; Pérez, S; Crespo, J; Remohí, J; Pellicer, A

2008-05-01

Oocyte cryopreservation is a useful tool for preserving the fertility of cancer patients at risk of losing ovarian function due to undergoing potentially sterilising therapies. Results obtained with different cryopreservation protocols have been disappointing, particularly those obtained with slow cooling procedures. The efficacy of vitrification as an application in clinical practice has recently been demonstrated. The aim of this study is to report results obtained with the Cryotop method of oocyte vitrification in a population of healthy women and to point out its potential usefulness for fertility preservation in oncological patients. The study population consisting of non-oncological patients included 47 oocyte donors and 57 recipients undergoing an oocyte donation cycle of assisted reproductive technology (ART). A total of 693 mature metaphase II oocytes were collected following ovarian stimulation using long protocol down-regulation plus gonadotropin administration. Vitrification was carried out by means of the Cryotop method. Oocytes were donated to a compatible recipient after endometrial preparation. Of the 693 oocytes, 666 (96.1%) survived. A total of 487 (73.1%) were fertilised successfully. One hundred and seventeen embryos were transferred to 57 recipients. Pregnancy rate per transfer and implantation rates were 63.2% and 38.5% respectively. Twenty-eight healthy babies were later born. Oocyte cryo-banking by means of the Cryotop vitrification method represents a viable option for healthy women, producing excellent survival rates and a clinical outcome similar to that obtained with fresh oocytes. This approach could potentially be used in cancer patients who want to safeguard their fertility. Cancer patients could potentially benefit from this approach by storing their oocytes before the onset of the oncological therapy.
Malignant glioma--a nemesis which requires clinical and basic investigation in radiation oncology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davis, L.W.

1989-06-01

Malignant gliomas account for 40% of all central nervous system malignancies. These are essentially localized neoplastic tumors that have defied most treatment. In spite of improved techniques, surgery is unlikely to increase survival further since true cancer operations cannot be performed. Radiation therapy has made a significant difference in outcome. Investigation in radiation oncology is essential for further improvement in the treatment of these tumors. The pattern of failure is local tumor recurrence, but the method to overcome this resistance to treatment is not clear. Radiation therapy techniques and inherent radio-resistance have been considered as possible reasons for failure. Withmore » newer imaging procedures, the extent of tumor can be more accurately defined allowing improved treatment planning. Identifying an effective treatment program is more difficult. Studies have documented the beneficial effect of radiation therapy, but the optimal dose or fractionation schedule has not been determined. Whereas some studies have reported improved survival using higher radiation doses, others have reported no benefit. More recently, studies of multiple daily fractionation schedules have been conducted using two or three daily fractions. Equally confusing results have been reported. Histologically, these tumors have necrotic areas and may be radioresistant due to hypoxic cells. Treatment methods designed to overcome the radioprotective effect of hypoxia have yielded disappointing results. The addition of hypoxic cell sensitizers has not produced the expected improvement in outcome. Studies using neutron radiation therapy report tumor control but not improved survival. Radiobiologic information is now available which may contribute to our understanding of the response of these tumors to radiation. Further laboratory and clinical investigation is required. 83 references.« less
A Review of GM-CSF Therapy in Sepsis

PubMed Central

Mathias, Brittany; Szpila, Benjamin E.; Moore, Frederick A.; Efron, Philip A.; Moldawer, Lyle L.

2015-01-01

Abstract Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient. Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS). Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent. The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs. PMID:26683913
NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.

PubMed

Diluvio, Giulia; Del Gaudio, Francesca; Giuli, Maria Valeria; Franciosa, Giulia; Giuliani, Eugenia; Palermo, Rocco; Besharat, Zein Mersini; Pignataro, Maria Gemma; Vacca, Alessandra; d'Amati, Giulia; Maroder, Marella; Talora, Claudio; Capalbo, Carlo; Bellavia, Diana; Checquolo, Saula

2018-05-25

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

Causal Scale of Rotors in a Cardiac System

NASA Astrophysics Data System (ADS)

Ashikaga, Hiroshi; Prieto-Castrillo, Francisco; Kawakatsu, Mari; Dehghani, Nima

2018-04-01

Rotors of spiral waves are thought to be one of the potential mechanisms that maintain atrial fibrillation (AF). However, disappointing clinical outcomes of rotor mapping and ablation to eliminate AF raise a serious doubt on rotors as a macro-scale mechanism that causes the micro-scale behavior of individual cardiomyocytes to maintain spiral waves. In this study, we aimed to elucidate the causal relationship between rotors and spiral waves in a numerical model of cardiac excitation. To accomplish the aim, we described the system in a series of spatiotemporal scales by generating a renormalization group, and evaluated the causal architecture of the system by quantifying causal emergence. Causal emergence is an information-theoretic metric that quantifies emergence or reduction between micro- and macro-scale behaviors of a system by evaluating effective information at each scale. We found that the cardiac system with rotors has a spatiotemporal scale at which effective information peaks. A positive correlation between the number of rotors and causal emergence was observed only up to the scale of peak causation. We conclude that rotors are not the universal mechanism to maintain spiral waves at all spatiotemporal scales. This finding may account for the conflicting benefit of rotor ablation in clinical studies.
Diagnostic relevance of high field MRI in clinical neuroradiology: the advantages and challenges of driving a sports car.

PubMed

Wattjes, Mike P; Barkhof, Frederik

2012-11-01

High field MRI operating at 3 T is increasingly being used in the field of neuroradiology on the grounds that higher magnetic field strength should theoretically lead to a higher diagnostic accuracy in the diagnosis of several disease entities. This Editorial discusses the exhaustive review by Wardlaw and colleagues of research comparing 3 T MRI with 1.5 T MRI in the field of neuroradiology. Interestingly, the authors found no convincing evidence of improved image quality, diagnostic accuracy, or reduced total examination times using 3 T MRI instead of 1.5 T MRI. These findings are highly relevant since a new generation of high field MRI systems operating at 7 T has recently been introduced. • Higher magnetic field strengths do not necessarily lead to a better diagnostic accuracy. • Disadvantages of high field MR systems have to be considered in clinical practice. • Higher field strengths are needed for functional imaging, spectroscopy, etc. • Disappointingly there are few direct comparisons of 1.5 and 3 T MRI. • Whether the next high field MR generation (7 T) will improve diagnostic accuracy has to be investigated.
Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

PubMed

Fox, Robert J; Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-11-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.
Molecular Basis of Cardioprotective Effect of Antioxidant Vitamins in Myocardial Infarction

PubMed Central

Rodrigo, Ramón; Feliú, Felipe; Hasson, Daniel

2013-01-01

Acute myocardial infarction (AMI) is the leading cause of mortality worldwide. Major advances in the treatment of acute coronary syndromes and myocardial infarction, using cardiologic interventions, such as thrombolysis or percutaneous coronary angioplasty (PCA) have improved the clinical outcome of patients. Nevertheless, as a consequence of these procedures, the ischemic zone is reperfused, giving rise to a lethal reperfusion event accompanied by increased production of reactive oxygen species (oxidative stress). These reactive species attack biomolecules such as lipids, DNA, and proteins enhancing the previously established tissue damage, as well as triggering cell death pathways. Studies on animal models of AMI suggest that lethal reperfusion accounts for up to 50% of the final size of a myocardial infarct, a part of the damage likely to be prevented. Although a number of strategies have been aimed at to ameliorate lethal reperfusion injury, up to date the beneficial effects in clinical settings have been disappointing. The use of antioxidant vitamins could be a suitable strategy with this purpose. In this review, we propose a systematic approach to the molecular basis of the cardioprotective effect of antioxidant vitamins in myocardial ischemia-reperfusion injury that could offer a novel therapeutic opportunity against this oxidative tissue damage. PMID:23936799
Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

PubMed Central

Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-01-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. PMID:22917690
[Childbirth without pain. Politics in France during the cold war. ].

PubMed

Caron-Leulliez, Marianne

2006-01-01

Dr. Lamaze introduced Natural Childbirth (ASD) in France in 1951. While this event is significant to the history of obstetrics and women's experience, we would like to concentrate upon another aspect here: how it is situated within the political debates of the period. In the midst of the Cold War, Lamaze was a sympathizer, although not a member of the Communist Party (PCF). He ran a maternity clinic for the CGT, a union affiliated with the PCE During a trip to Russia in 1951, he discovered a new method to relieve pain in labour through a psychological technique inspired by Pavlov. Upon his return, when he dedicated his energies towards the popularization of ASD, he looked for support from the PCF and to draw upon their propaganda network; this subsequently aroused suspicion and hostility. A few years later, ASD received the blessing of women's groups won over by its improvements to birthing. At the moment of Lamaze's triumph, he fell victim to a resurgence of Stalinism. With his team, he denounced the Soviet invasion of Hungary and lost the financial support of the unions which owned the clinic. Exhausted and profoundly disappointed, he died in March 1957.
Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities.

PubMed

Xiong, Ye; Mahmood, Asim; Chopp, Michael

2018-06-01

Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and promote functional recovery after TBI. Copyright © 2018 Daping Hospital and the Research Institute of Surgery of the Third Military Medical University. Production and hosting by Elsevier B.V. All rights reserved.
Coenzyme Q 10 improves lactic acidosis, strokelike episodes, and epilepsy in a patient with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes).

PubMed

Berbel-Garcia, Angel; Barbera-Farre, Jose Ramon; Etessam, Jesús Porta; Salio, Antonio Martínez; Cabello, Ana; Gutierrez-Rivas, Eduardo; Campos, Yolanda

2004-01-01

Mitochondrial encephalomyopathies encompass a group of disorders that have impaired oxidative metabolism in skeletal muscles and central nervous system. Many compounds have been used in clinical trials on mitochondrial diseases, but the outcomes have been variable. It remains controversial whether treatment of mitochondrial diseases with coenzyme Q 10 is effective. This paper describes a case of mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes, and exercise intolerance successfully treated with coenzyme Q 10. Efficacy of this therapy in this patient is correlated to control of lactic acidosis and serum creatine kinase levels. Disappointingly, larger studies with coenzyme Q 10 failed to demonstrate a clear beneficial effect on the entire study population with regard to clinical improvement or several parameters of the oxidative metabolism. They suggest that the use of coenzyme Q in treatment of mitochondrial diseases should be confined to protocols. There is a confounding variation in phenotype and genotype, and the natural history of the disorders in individual patients is not accurately predictable. The unpredictable a priori efficacy of therapy suggests that a long-term trial of oral coenzyme Q may be warranted.
The magnificent outburst of the 2016 Perseids, the analyses

NASA Astrophysics Data System (ADS)

Miskotte, Koen; Vandeputte, Michel

2017-03-01

Enhanced Perseid activity had been predicted for 2016 as a result of a sequence of encounters with some dust trails as well as the effect of perturbations by Jupiter which made Earth crossing the main stream deeper through more dense regions. Visual observations resulted in a detailed activity profile and population index profile, the observed features in these profiles could be matched with the predicted passages through the different dust trails. The 4 Rev (1479) dust trail in particular produced a distinct peak while the 7 Rev (1079) dust trail remained rather at a somehow disappointing low level. The traditional annual Perseid maximum displayed enhanced activity due to the 12 Rev (441) dust trail.
Epigallocatechin-3-gallate reduces DNA damage induced by benzo[a]pyrene diol epoxide and cigarette smoke condensate in human mucosa tissue cultures.

PubMed

Baumeister, Philipp; Reiter, Maximilian; Kleinsasser, Norbert; Matthias, Christoph; Harréus, Ulrich

2009-06-01

Although epidemiological studies indicate cancer preventive effects of diets rich in fruit and vegetables, large clinical intervention studies conducted to evaluate dietary supplementation with micronutrients, mostly vitamins, showed disappointing results in large parts. In contrast, there is encouraging epidemiologic data indicating great chemopreventive potential of a large group of phytochemicals, namely polyphenols. This study shows the DNA protective effect epigallocatechin-3-gallate, a tea catechin, and one of the best-studied substances within this group, on carcinogen-induced DNA fragmentation in upper aerodigestive tract cells. Cell cultures from fresh oropharyngeal mucosa biopsies were preincubated with epigallocatechin-3-gallate in different concentrations before DNA damage was introduced with the metabolically activated carcinogen benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide or cigarette smoke condensate. Effects on resulting DNA fragmentation were measured using the alkaline single-cell microgel electrophoresis (comet assay). Epigallocatechin-3-gallate significantly reduced benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced DNA damage by up to 51% (P<0.001). Fragmentation induced by cigarette smoke condensate could be lowered by 47% (P<0.001). Data suggest a cancer preventive potential of epigallocatechin-3-gallate as demonstrated on a subcellular level. An additional mechanism of tea catechin action is revealed by using a primary mucosa culture model.
THE USE OF IODINE-125 AS A DIAGNOSTIC AGENT IN OPHTHALMOLOGY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Newell, F.W.; Goren, S.B.; Brizel, H.E.

The use of radioactive isotopes in ophthalmoiogy has been restricted by the physical properties of the radioactive compounds available. Beta-emitting compounds, such as radiophosphorus (P/sup 32/), are mainly useful in abnormalities of the anterior ocular segment. Gamma-emitting compounds are of value only if significant quantities are retained by ocular tissue, with the remainder being rapid excreted. Under these conditions, the radioactive target within the eye would not be obscured by surrounding radi tion, particularly that emanating from the intracranial circulation. Although P/sup 32/ has often been useful in the diagnosis of anterior segment neoplasms, its application to posterior segment andmore » orbital tumors has been disappoint ing. Subconjunctival dissection, rotation of the globe, an curved probes sometimes allow counting over the lesion but often do not. The probe used to measure the radioactivity must be in close proximity to the neoplasm. The test has proved to be of no value in the differential diagnosis of retinoblastoma. Its accuracy is reduced in the presence of active ocular inflammatory disease, following ocular surgery, and in one-eyed patients. Characteristics favorable to clinical use of radioisotopes are listed. lodine-125 in most of these respects qualifies as an excellent isotope for ocular use. It may be substituted advantageously for P/sup 32/ or I/ sup 131/ in many clinical and experimental situations in ophthalmology. The use of diiodofluorescein labeled with I/sup 125/ for detection of intraocular tumors is described; the procedure for its use is given in detail; and results in 39 patients are revealed. In the 19 patients with histologic evidence of neoplasm the test was correctly positive in 15 and a false negative result occurred in 4, an overall accuracy of 79%. In 20 patients with a variety of non-neoplastic ocular diseases there were no positive tests. Successful results are also reported on the efficacy of I/sup 125/-labeled diiodofluorescein as a diagnostic agent in the laboratory, the V-2 rabbit carcinoma being used as an experimental model. Clinical results of tests using I/sup 125/labeled tetracycline are also described. (BBB)« less
Interview Experiences and Diversity Concerns of Counselor Education Faculty from Underrepresented Groups

ERIC Educational Resources Information Center

Cartwright, Angie D.; Avent-Harris, Janeé R.; Munsey, Rebecca Beck; Lloyd-Hazlett, Jessica

2018-01-01

The authors used transcendental phenomenology to explore the campus interview experiences and diversity concerns of counselor education faculty from underrepresented populations. Six themes were identified: issues of integrity, disappointment in the counseling profession, importance of authenticity, intersectionality of major identity markers,…
Non-editorial Conversation

ERIC Educational Resources Information Center

Whitehouse, John

1974-01-01

In his position as retiring chief of the Workers' Education Branch of the International Labour Office (ILO), Paul B. J. Chu is interviewed on worker education, the ILO organization and tole, personal disappointments and satisfactions, future educational developments in which the ILO will be involved, and problems facing workers' education. (AG)
The Direction of Web-based Training: A Practitioner's View.

ERIC Educational Resources Information Center

Kilby, Tim

2001-01-01

Web-based training has had achievements and disappointments as online learning has matured. Best practices include user-centered design, knowledge object structures, usability engineering, and formal evaluation. Knowledge management, peer-to-peer learning, and personal learning appliances will continue to alter the online learning landscape. (SK)
Meeting the Challenge of Mathematics Reform for Students with LD.

ERIC Educational Resources Information Center

Woodward, John; Montague, Marjorie

2002-01-01

This article discusses forces driving mathematics reform: shifting theoretical paradigms, disappointing levels of mathematics performance of students in the United States, and the impact of rapidly changing technologies. Concerns about this reform from the special education community are discussed, and synthesized special education research…
A Bad Argument for a Reasonable Position

ERIC Educational Resources Information Center

Bain, Robert B.

2008-01-01

The author was disappointed after reading Kevin St. Jarre's article entitled "Reinventing Social Studies". Rather than reinventing social studies, this article reflects the field's major problems. It recycles stereotypical views of history teachers, confuses chronology with history, and offers a one-dimensional, single-cause explanation for how…
Rural Areas in the Information Society: Diminishing Distance or Increasing Learning Capacity?

ERIC Educational Resources Information Center

Grimes, Seamus

2000-01-01

Examines prospects for rural areas within the Information Society, referring particularly to the European Union. Discusses effects of diminished distance from core markets, increased learning capacity through improved access to information, public policy emphasis on building infrastructure, disappointing outcomes for telecommunications initiatives…
Stepping Forward

ERIC Educational Resources Information Center

Lum, Lydia

2005-01-01

As Butler University President Bobby Fong was reviewing applications a few years ago for a national fellows program that grooms future leaders of higher education, he casually asked how many Asian Pacific Americans (APAs) were under consideration. None. The reason was that not one applied. A disappointed Fong urged the American Council on…
Japanese Inspired Customer Service

ERIC Educational Resources Information Center

Lonabocker, Louise

2004-01-01

The author of this commentary was looking forward to visiting Japan, a new culture. With excitement she anticipated experiencing hot springs, monumental shrines, breathtaking gardens, delicious sashimi and soba, and the speedy bullet trains--all so different from life in Boston. She was not disappointed but was surprised, pleasantly, by constant…
Sweat, Brain-Power, Horsepower, and Time - The Keys to Controlling Weeds

USDA-ARS?s Scientific Manuscript database

Weed control in organic crop production is difficult and costly. Early studies on organic weed control in conservation tillage systems were disappointing. Research shifted to organic weed control in conventional tillage systems. Intense cultivation with a tine weeder was the most consistent metho...

Solitary Learner in Online Collaborative Learning: A Disappointing Experience?

ERIC Educational Resources Information Center

Ke, Fengfeng; Carr-Chellman, Alison

2006-01-01

Research suggests that the solitary learner's learning preferences might be a mismatch with collaborative instructional settings. A question is therefore posed: "In online learning environments that require collaboration, how do solitary learners experience their own learning?" It is important to answer this question to understand and…
Identity Work at a Normal University in Shanghai

ERIC Educational Resources Information Center

Cockain, Alex

2016-01-01

Based upon ethnographic research, this article explores undergraduate students' experiences at a normal university in Shanghai focusing on the types of identities and forms of sociality emerging therein. Although students' symptoms of disappointment seem to indicate the power of university experiences to extinguish purposeful action, this article…
Stop misbehaving!

PubMed Central

Neill, Ushma S.

2006-01-01

Scientists are usually thought to be beyond reproach, but with the recent spate of high-profile ethical transgressions by scientists, the public’s trust in science and scientists is deteriorating. The numerous cases of scientific misconduct that have crossed my desk in the last year leave me disenchanted, disappointed, and disillusioned. PMID:16823470
Ethical challenges in conducting clinical research in lung cancer

PubMed Central

Tod, Angela M.

2016-01-01

The article examines ethical challenges that arise with clinical lung cancer research focusing on design, recruitment, conduct and dissemination. Design: problems related to equipoise can arise in lung cancer studies. Equipoise is an ethics precondition for RCTs and exists where there is insufficient evidence to decide which of two or more treatments is best. Difficulties arise in deciding what level of uncertainty constitutes equipoise and who should be in equipoise, for example, patients might not be even where clinicians are. Patient and public involvement (PPI) can reduce but not remove the problems. Recruitment: (I) lung cancer studies can be complex, making it difficult to obtain good quality consent. Some techniques can help, such as continuous consent. But researchers should not expect consent to be the sole protection for participants’ welfare. This protection is primarily done elsewhere in the research process, for example, in ethics review; (II) the problem of desperate volunteers: some patients only consent to a trial because it gives them a 50/50 option of the treatment they want and can be disappointed or upset if randomised to the other arm. This is not necessarily unfair, given clinical equipoise. However, it should be avoided where possible, for example, by using alternative trial designs; (III) the so-called problem of therapeutic misconception: this is the idea that patients are mistaken if they enter trials believing this to be in their clinical best interest. We argue the problem is misconceived and relates only to certain health systems. Conduct: lung cancer trials face standard ethical challenges with regard to trial conduct. PPI could be used in decisions about criteria for stopping rules. Dissemination: as in other trial areas, it is important that all results, including negative ones, are reported. We argue also that the role of PPI with regard to dissemination is currently under-developed. PMID:27413698
Alveolar nerve repositioning with rescue implants for management of previous treatment. A clinical report.

PubMed

Amet, Edward M; Uehlein, Chris

2013-12-01

The goal of modern implant dentistry is to return patients to oral health in a rapid and predictable fashion, following a diagnostically driven treatment plan. If only a limited number of implants can be placed, or some fail and the prosthetic phase of implant dentistry is chosen to complete the patient's treatment, the final outcome may result in partial patient satisfaction and is commonly referred to as a "compromise." Previous All-on-4 implant treatment for the patient presented here resulted in a compromise, with an inadequate support system for the mandibular prosthesis and a maxillary complete denture with poor esthetics. The patient was unable to function adequately and also was disappointed with the resulting appearance. Correction of the compromised treatment consisted of bilateral inferior alveolar nerve elevation and repositioning without bone removal for lateral transposition, to gain room for rescue implants for a totally implant-supported and stabilized prosthesis. Treatment time to return the patient to satisfactory comfort, function, facial esthetics, and speech was approximately 2 weeks. The definitive mandibular prosthesis was designed for total implant support and stability with patient retrievability. Adequate space between the mandibular bar system and the soft tissue created a high water bridge effect for self-cleansing. Following a short interim mandibular healing period, the maxillary sinuses were bilaterally grafted to compensate for bone inadequacies and deficiencies for future maxillary implant reconstruction. © 2013 by the American College of Prosthodontists.
Insulin signaling pathways in a patient with insulin resistance of difficult management - a case report

PubMed Central

2009-01-01

Insulin signalling pathways were investigated in a 33 year-old woman with immunologic insulin resistance. Her past medical history was remarkable for intermittent use of insulin and allergic reactions to several drugs, and measure of plasma anti-insulin antibodies level corroborated the clinical suspicion of immune mediated insulin resistance (8074 nU/ml - RIA - Ref value: <60). Treatment with several immunosuppressive regimens was tried, however the results were disappointing. Possible subcellular mechanisms of insulin resistance were investigated by performing analysis of insulin receptor and post receptor signaling in skeletal muscle biopsy. The expression of insulin receptor (IR), insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT-4) was evaluated in total extract from muscle tissue by Western blotting. Basal IR, IRS-1 and GLUT-4 expression was detected, however receptor autophosphorylation was not observed. A study of translocation of GLUT-4 to plasma membrane showed that tissue presented low levels of membrane-associated GLUT-4. When in vitro stimulation was undertaken, tissue was capable to be responsive to insulin. Our results suggest that even though IR expression was normally occurring, IR β-subunit tyrosine kinase activity in muscle was down-regulated leading to alterations in insulin post receptor signaling. Consistent with normal insulin receptor and post receptor signaling, our results were compatible with decreased insulin binding to IR probably due to neutralization by anti-insulin antibodies. In conclusion, this patient has immunologic insulin resistance and treatment should be based on immunosuppressive drugs as tolerated. PMID:19941665
Nonablative laser resurfacing: state of the art 2002.

PubMed

Pozner, Jason N; Goldberg, David J

2002-09-01

The reader is presumed to have a basic understanding of the use of lasers in plastic surgery and laser physics. After reading this article, the participant should be able to: Physicians may earn 1 hour of Category 1 CME credit by successfully completing the examination on the basis of material covered in this article. The examination begins on page 435. Nonablative resurfacing, also referred to as subsurface or dermal remodeling, is a recently introduced technology for restoring damaged collagen without injuring or removing the overlying epidermis. To date there have been no published comparisons or reviews of these laser systems. The authors review the mechanisms of action of currently available nonablative laser technologies and published data on their performance. Literature concerning nonablative laser technology published between 2000 and 2002 was reviewed by use of Medline searches. Data on technical specifications were obtained from the manufacturers. Significant improvement in skin elasticity and photodamage with few or no complications was noted after treatment with most of the systems reviewed. However, the results were generally more subtle than those achieved with ablative lasers. Nonablative technology is currently at the forefront of skin rejuvenation. Data on long-term results must await several more years of accumulated clinical treatment. Improvement in skin quality, tone, and texture can be expected, but patients and physicians who expect nonablative laser treatment results to be similar to those achieved by ablative techniques may be disappointed. (Aesthetic Surg J 2002;22:427-434.).
Combination alpha-interferon and lamivudine therapy for alpha-interferon-resistant chronic hepatitis B infection: results of a pilot study.

PubMed

Mutimer, D; Naoumov, N; Honkoop, P; Marinos, G; Ahmed, M; de Man, R; McPhillips, P; Johnson, M; Williams, R; Elias, E; Schalm, S

1998-06-01

Alpha-interferon achieves seroconversion in about one third of naive patients. Attempts to achieve seroconversion in patients who have previously failed alpha-interferon have proved disappointing. Combination chemotherapy (alpha-interferon with a nucleoside analogue) might provide a treatment alternative for these patients. We have undertaken a phase 2 study in 20 patients who had previously failed at least one course of alpha-interferon. The study was designed to assess the safety, tolerability and efficacy of the combination. All patients were treated for 16 weeks with alpha-interferon in combination with 12 or 16 weeks of Lamivudine (3'TC). Patients were followed for 16 weeks post-treatment. Pharmacokinetic studies were performed to identify/exclude significant pharmacokinetic drug interaction. The combination was well tolerated, and side-effects of the combination were indistinguishable from the recognised side-effects of alpha-interferon. Pharmacokinetic studies performed on days 1 and 29 did not show any significant interaction. All patients achieved HBV DNA clearance during treatment, but 19 relapsed at the end of treatment. HBeAg/anti-HBe seroconversion was observed for four patients, but was sustained for a single patient (who also had sustained DNA clearance). Combination therapy with alpha-interferon and lamivudine given for 16 weeks appears safe and is well tolerated. However, for this group of patients who had previously failed interferon monotherapy, the efficacy of combination interferon/lamivudine therapy appears disappointing, and other treatment strategies should be investigated.
Social and Contextual Influences on Mental Health Following an Episode of Mass Violence.

PubMed

Felix, Erika D; Moore, Stephanie A; Meskunas, Haley; Terzieva, Antoniya

2017-11-01

Few studies explore how the recovery context following an episode of mass violence affects posttragedy mental health (MH), despite clear implications for developing posttrauma supports. Following a mass murder, this prospective, longitudinal study examined how reactions to media coverage, family reactions, and disappointment in social support influenced posttragedy MH (posttraumatic stress, depression, anxiety), above and beyond the influence of pretragedy MH, pretragedy victimization, and objective exposure. University students who participated in a study of college adjustment prior to the mass murder ( n = 593) were recontacted and provided information on their posttragedy life ( n = 142). Students ( n = 84) also responded to open-ended questions about what was the most stressful part of the tragedy and psychological effects of the mass murder. After accounting for pretragedy victimization and MH, and objective exposure to events, hierarchical regression analyses indicated that distress related to media coverage and stronger family reactions contributed to higher levels of posttraumatic stress symptoms and anxiety, but not depression. Disappointment with social support was not significantly related to posttragedy MH. Common themes in student comments include grief, feeling vulnerable/unsafe, concern for the impact on others, stress related to media coverage, proximity to the events, changes in psychosocial adjustment, and returning to daily life. Results suggest that negative reactions to media coverage and family reactions that are overprotective or distressing negatively affect survivors' MH, beyond their objective exposure to the violence, pretragedy MH, and pretragedy victimization.
Appraising the methodological quality of the clinical practice guideline for diabetes mellitus using the AGREE II instrument: a methodological evaluation.

PubMed

Radwan, Mahmoud; Akbari Sari, Ali; Rashidian, Arash; Takian, Amirhossein; Abou-Dagga, Sanaa; Elsous, Aymen

2017-02-01

To evaluate the methodological quality of the Palestinian Clinical Practice Guideline for Diabetes Mellitus using the Translated Arabic Version of the AGREE II. Methodological evaluation. A cross-cultural adaptation framework was followed to translate and develop a standardised Translated Arabic Version of the AGREE II. Palestinian Primary Healthcare Centres. Sixteen appraisers independently evaluated the Clinical Practice Guideline for Diabetes Mellitus using the Translated Arabic Version of the AGREE II. Methodological quality of diabetic guideline. The Translated Arabic Version of the AGREE II showed an acceptable reliability and validity. Internal consistency ranged between 0.67 and 0.88 (Cronbach's α). Intra-class coefficient among appraisers ranged between 0.56 and 0.88. The quality of this guideline is low. Both domains 'Scope and Purpose' and 'Clarity of Presentation' had the highest quality scores (66.7% and 61.5%, respectively), whereas the scores for 'Applicability', 'Stakeholder Involvement', 'Rigour of Development' and 'Editorial Independence' were the lowest (27%, 35%, 36.5%, and 40%, respectively). The findings suggest that the quality of this Clinical Practice Guideline is disappointingly low. To improve the quality of current and future guidelines, the AGREE II instrument is extremely recommended to be incorporated as a gold standard for developing, evaluating or updating the Palestinian Clinical Practice Guidelines. Future guidelines can be improved by setting specific strategies to overcome implementation barriers with respect to economic considerations, engaging of all relevant end-users and patients, ensuring a rigorous methodology for searching, selecting and synthesising the evidences and recommendations, and addressing potential conflict of interests within the development group.
School and University in Soviet Cinema of "Perestroika" (1986-1991)

ERIC Educational Resources Information Center

Fedorov, Alexander; Levitskaya, Anastasia; Gorbatkova, Olga; Mamadaliev, Anvar

2018-01-01

Films of the "perestroika" period (1986-1991) related to school/university theme showed that: - the educational / upbringing process has lost the previous strict storylines and in many respects has lost its communist landmarks;--both school and university have acute problem areas (crisis, disappointment and fatigue, professional…
A strange cat in Dublin

NASA Astrophysics Data System (ADS)

O'Raifeartaigh, Cormac

2012-11-01

Not many life stories in physics involve Nazis, illicit sex, a strange cat and the genetic code. Thus, a new biography of the great Austrian physicist Erwin Schrödinger is always of interest, and with Erwin Schrödinger and the Quantum Revolution, veteran science writer John Gribbin does not disappoint.
Social Group Membership Increases STEM Engagement among Preschoolers

ERIC Educational Resources Information Center

Master, Allison; Cheryan, Sapna; Meltzoff, Andrew N.

2017-01-01

The American educational system currently yields disappointing levels of science, technology, engineering, and math (STEM) engagement and achievement among students. One way to remedy this may be to increase children's motivation in STEM from an early age. This study examined whether a social cue--being part of an experimental "minimal…
Consonance in Information System Projects: A Relationship Marketing Perspective

ERIC Educational Resources Information Center

Lin, Pei-Ying

2010-01-01

Different stakeholders in the information system project usually have different perceptions and expectations of the projects. There is seldom consistency in the stakeholders' evaluations of the project outcome. Thus the outcomes of information system projects are usually disappointing to one or more stakeholders. Consonance is a process that can…
Counselling Challenges and Strategies for Cochlear Implant Specialists

ERIC Educational Resources Information Center

English, Kris

2010-01-01

Cochlear implant specialists daily observe patients and families grapple with a wide range of emotions. As nonprofessional counsellors, we can help patients address those emotions by providing more opportunities to talk about their thoughts and feelings. This paper will review some familiar counselling challenges, such as the disappointment that…
The Labour Party's Blunkett Review: A Comprehensive Disappointment

ERIC Educational Resources Information Center

Lichman, Keith

2014-01-01

David Blunkett's "Review of Education Structures" for the Labour Party recognises that there is a chaotic and unsatisfactory situation in the English education system but its response is ambiguous and self-contradictory. Its proposals seek to normalise and regulate rather than remedy a system in which lack of democratic accountability,…
Teaching: From Disappointment to Ecstasy

ERIC Educational Resources Information Center

Albers, Cheryl

2009-01-01

Unintended outcomes can derail the best of intentions in the classroom. Designing a new course for Honors students provided an opportunity to change my traditional teaching style. I envisioned a classroom where students enthusiastically became more self-directed learners. I was perplexed with mixed reactions from students; while some joined me and…
Postdoctoral Appointments and Disappointments.

ERIC Educational Resources Information Center

National Academy of Sciences - National Research Council, Washington, DC. Commission on Human Resources.

Detailed findings on a broad range of issues concerning the importance of postdoctorals to the nation's research effort and the value of postdoctoral experience to young scientists and engineers pursuing careers in research are presented. The report, the first comprehensive study of postdoctorals in 10 years, identifies the following issues: (1)…
A Reply to John Searle and Other Traditionalists

ERIC Educational Resources Information Center

Brice, Robert Greenleaf

2008-01-01

In an article entitled "Traditionalists & Their Challengers," John Searle says there is "supposed to be a major debate" in the universities as to whether liberal education should be replaced with multiculturalism. He finds this debate "puzzling," "disappointing," even "depressing." By dividing academia into two groups, the so-called "defenders of…
On Conceptual Analysis as the Primary Qualitative Approach to Statistics Education Research in Psychology

ERIC Educational Resources Information Center

Petocz, Agnes; Newbery, Glenn

2010-01-01

Statistics education in psychology often falls disappointingly short of its goals. The increasing use of qualitative approaches in statistics education research has extended and enriched our understanding of statistical cognition processes, and thus facilitated improvements in statistical education and practices. Yet conceptual analysis, a…

The Mexican "Illegal Alien" Commute.

ERIC Educational Resources Information Center

Decker, Phil

1986-01-01

A photo report of the following three treks by illegal aliens across the border from Mexico to work in Arizona reveals the dangers and disappointments the migrants are exposed to: (1) a "carpool" from Southern Mexico; (2) a train ride from Sinaloa; and (3) a 40-mile hike through the Arizona desert. (PS)
High Schools at the Tipping Point

ERIC Educational Resources Information Center

Wise, Bob

2008-01-01

The U. S. high school system is in crisis, Wise argues. More than 1 million students drop out every year, significant numbers of college freshmen require remedial courses to handle college work, and employers consistently express disappointment in the skills of graduates. The high dropout rate and students' lack of preparedness carries…
Portrait Gallery Illuminates--Grant's Triumphs, Failures.

ERIC Educational Resources Information Center

Lambert, Robert G., Jr.

The 100th anniversary of Ulysses S. Grant's death was observed on July 23, 1985. The Smithsonian National Portrait Gallery featured an exhibit of Grant portraiture, which covered his life, from its humble beginnings to military and political triumphs and to failures and disappointment. The exhibit included pictures, artifacts, and momentos from…
A Potential Way of Enquiry into Human Curiosity

ERIC Educational Resources Information Center

Guo, Shesen; Zhang, Ganzhou; Zhai, Run

2010-01-01

A powerful search for "curiosity" or its related topics at the online American Psychological Association PsycNET database will produce comparatively disappointing meagreness of resource. This reflects our scanty knowledge in this field though curiosity is widely recognised as one of the most important factors that contribute to motivation and…
MOOC Success Factors: Proposal of an Analysis Framework

ERIC Educational Resources Information Center

Azevedo, José; Marques, Margarida Morais

2017-01-01

Aim/Purpose: From an idea of lifelong-learning-for-all to a phenomenon affecting higher education, Massive Open Online Courses (MOOCs) can be the next step to a truly universal education. Indeed, MOOC enrolment rates can be astoundingly high; still, their completion rates are frequently disappointingly low. Nevertheless, as courses, the…
The 1977 National Women's Conference in Houston--Gains and Disappointments for Hispanas.

ERIC Educational Resources Information Center

Burciaga, Cecilia P.

1978-01-01

The article presents the outcomes of the women's conference, not only as a single event, but also as an analysis of the dynamics that were, and are, currently operating in the women's movement vis-a-vis Hispanic women in general, and Chicanas in particular. (NQ)
Worldwide Report, Arms Control.

DTIC Science & Technology

1985-06-21

atmosphere of disappoint- ment," Koivisto said. It is, of course, sober realism to speak in this way. But the president himself showed that he has not...of journals known only to specialists to the front pages of newspapers all over the world. But this does not gladden us. It is not cinematic evil
Starsearch: A Teacher Recognition Program for You and Your Community.

ERIC Educational Resources Information Center

Jackson, Marc

Maintaining an effective school system means retaining the outstanding teachers supporting it. According to a recent survey, many southern California teachers felt they would be disappointed if their children entered the profession. In California alone, there are 49,000 inactive teachers. One problem may be student discipline. Whereas top…
A Lawyer-Therapist Team as Mediator in a Marital Crisis.

ERIC Educational Resources Information Center

Wiseman, Janet Miller; Fiske, John A.

1980-01-01

Whether the union is jeopardized by disappointment, fear of not achieving satisfaction in life, or other problems, the couple in crisis may turn to divorce as the lesser evil. The mediation process is of potential value to those couples who may want to avoid protracted, painful lawsuits. (Author)
Fad reducing diets: separating fads from facts.

PubMed

Blackburn, G L; Pavlou, K

1984-01-01

Generally, it is wise to stay away from any crash diet. All tend to be nutritionally unbalanced. Although all may cause great temporary weight losses in short periods of time, over the long term, the only thing they accomplish is the addition of another cycle of frustration and disappointment for the dieter.
Growth and Decline of Second Life as an Educational Platform

ERIC Educational Resources Information Center

Mark, Christine Libby

2014-01-01

"Second Life," a 3D online immersive virtual environment, emerged in 2003 and was predicted to become the predominant online course delivery platform by 2013. Educational institutions initially rushed to create a presence in the "Second Life;" however, after 2009 those same institutions were disappointed by their experiences…
Choosing War: The Decision to Invade Iraq and Its Aftermath

DTIC Science & Technology

2008-04-01

Ballard, a recent Iraq veteran, all contributed greatly. From the Institute for National Strategic Studies, Dr. Christopher J. Lamb , Dr. James A. Schear...reforms of 1986 were stewing for many years and were only enacted after a series of disappointing opera- tions in which the obvious national failure was
SYSTEMATISCHER AUSSPRACHEUNTERRICHT IM SPRACHLABORATORIUM (SYSTEMATIC PRONUNCIATION INSTRUCTION IN THE LANGUAGE LABORATORY).

ERIC Educational Resources Information Center

BOEDDINGHAUS, WALTER

THE APPARENT DISAPPOINTMENT AND SLACKENING OF ENTHUSIASTIC INTEREST IN LANGUAGE LABORATORY INSTRUCTION IS MOST PROBABLY NOT DUE TO A FUNDAMENTAL LACK OF EFFECTIVENESS, BUT TO METHODOLOGICAL AND ORGANIZATIONAL PROBLEMS YET TO BE SOLVED. MOST IMPORTANT, THE RESTRICTIVE DEPENDENCE OF LABORATORY MATERIAL ON CLASSROOM LESSONS MUST BE ABANDONED. ONLY…
Students Aren't What They Used to Be--and Never Were

ERIC Educational Resources Information Center

Watson, David

2010-01-01

Taking as his cue the House of Commons Select Committee for Innovation, Universities and Skills inquiry into "students and universities," the author begins by addressing four "pathologies" in the current discussion of the student experience: nostalgia and selective memory; condescension and disappointment; moral panic and…
The Role of Co-occurring Emotions and Personality Traits in Anger Expression

PubMed Central

Mill, Aire; Kööts-Ausmees, Liisi; Allik, Jüri; Realo, Anu

2018-01-01

The main aim of the current study was to examine the role of co-occurring emotions and their interactive effects with the Big Five personality traits in anger expression. Everyday anger expression (“anger-in” and “anger-out” behavior) was studied with the experience-sampling method in a group of 110 participants for 14 consecutive days on 7 random occasions per day. Our results showed that the simultaneously co-occurring emotions that buffer against anger expression are sadness, surprise, disgust, disappointment, and irritation for anger-in behavior, and fear, sadness and disappointment for anger-out reactions. While previous studies have shown that differentiating one's current affect into discrete emotion categories buffers against anger expression (Pond et al., 2012), our study further demonstrated the existence of specific interactive effects between the experience of momentary emotions and personality traits that lead to higher levels of either suppression or expression of anger behavior (or both). For example, the interaction between the trait Openness and co-occurring surprise, in predicting anger-in behavior, indicates that less open people hold their anger back more, and more open people use less anger-in behavior. Co-occurring disgust increases anger-out reactions in people low in Conscientiousness, but decreases anger-out reactions in people high in Conscientiousness. People high in Neuroticism are less likely to engage in anger-in behavior when experiencing disgust, surprise, or irritation alongside anger, but show more anger out in the case of co-occurring contempt. The results of the current study help to further clarify the interactions between the basic personality traits and the experience of momentary co-occurring emotions in determining anger behavior. PMID:29479333
[Burnout in officers of the prison service units. The role of personality and selected professional characteristics].

PubMed

Sygit-Kowalkowska, Ewa; Weber-Rajek, Magdalena; Herkt, Martyna; Ossowski, Roman

2017-02-28

The researchers involved in the studies of burnout indicate its 3 sources: the structure of the personality, the specificity of interpersonal relationships, and the organizational factors. The aim of this study was to evaluate the occurrence of burnout and personality characteristics of prison officers, as well as to determine predictors of burnout in this occupational group. The study was conducted among prison officers, who were divided into 2 groups, the officers working in direct contact with prisoners (group I) and those employed in the prison administration (group II). The study used 2 tools: NEO-Five Factor Inventory (NEO-FFI) and Link Burnout Questionnaire (LBQ). Analysis of personality traits in the study group showed high severity traits of neuroticism, extraversion, openness, agreeableness and conscientiousness. However, the best results were obtained in terms of extraversion and the lowest in the range of conscientiousness. The level of burnout in both groups was found to be within the upper limit of the average results, without statistically significant differences between the groups. The results showed that people working in direct contact with prisoners experience greater disappointments and psychophysical exhaustion at work. The analyses showed that the level of exhaustion and disappointment of the employees surveyed increases with increasing seniority. It was also shown that the level of neuroticism, extraversion and agreeableness is the predictor of effectiveness. The level of burnout in the study group falls within the upper limit of the average results. Personality traits are an important determinant for the development of symptoms of burnout in the penitentiary officers, and their role changes over the years of continuous prison service. The position at work diversifies the degree of experiencing symptoms of burnout. Med Pr 2017;68(1):85-94. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.
NK1 receptor antagonism and emotional processing in healthy volunteers.

PubMed

Chandra, P; Hafizi, S; Massey-Chase, R M; Goodwin, G M; Cowen, P J; Harmer, C J

2010-04-01

The neurokinin-1 (NK(1)) receptor antagonist, aprepitant, showed activity in several animal models of depression; however, its efficacy in clinical trials was disappointing. There is little knowledge of the role of NK(1) receptors in human emotional behaviour to help explain this discrepancy. The aim of the current study was to assess the effects of a single oral dose of aprepitant (125 mg) on models of emotional processing sensitive to conventional antidepressant drug administration in 38 healthy volunteers, randomly allocated to receive aprepitant or placebo in a between groups double blind design. Performance on measures of facial expression recognition, emotional categorisation, memory and attentional visual-probe were assessed following the drug absorption. Relative to placebo, aprepitant improved recognition of happy facial expressions and increased vigilance to emotional information in the unmasked condition of the visual probe task. In contrast, aprepitant impaired emotional memory and slowed responses in the facial expression recognition task suggesting possible deleterious effects on cognition. These results suggest that while antagonism of NK(1) receptors does affect emotional processing in humans, its effects are more restricted and less consistent across tasks than those of conventional antidepressants. Human models of emotional processing may provide a useful means of assessing the likely therapeutic potential of new treatments for depression.
Should Body Weight–Supported Treadmill Training and Robotic-Assistive Steppers for Locomotor Training Trot Back to the Starting Gate?

PubMed Central

Dobkin, Bruce H.; Duncan, Pamela W.

2014-01-01

Body weight–supported treadmill training (BWSTT) and robotic-assisted step training (RAST) have not, so far, led to better outcomes than a comparable dose of progressive over-ground training (OGT) for disabled persons with stroke, spinal cord injury, multiple sclerosis, Parkinson’s disease, or cerebral palsy. The conceptual bases for these promising rehabilitation interventions had once seemed quite plausible, but the results of well-designed, randomized clinical trials have been disappointing. The authors reassess the underpinning concepts for BWSTT and RAST, which were derived from mammalian studies of treadmill-induced hind-limb stepping associated with central pattern generation after low thoracic spinal cord transection, as well as human studies of the triple crown icons of task-oriented locomotor training, massed practice, and activity-induced neuroplasticity. The authors retrospectively consider where theory and practice may have fallen short in the pilot studies that aimed to produce thoroughbred interventions. Based on these shortcomings, the authors move forward with recommendations for the future development of workhorse interventions for walking. In the absence of evidence for physical therapists to employ these strategies, however, BWSTT and RAST should not be provided routinely to disabled, vulnerable persons in place of OGT outside of a scientifically conducted efficacy trial. PMID:22412172
[Immunotherapy in epithelial ovarian carcinoma: hope and reality].

PubMed

Lavoué, V; Foucher, F; Henno, S; Bauville, E; Catros, V; Cabillic, F; Levêque, J

2014-03-01

Epithelial ovarian carcinoma (EOC) has a worst prognosis with little progress in terms of survival for the last two decades. Immunology received little interest in EOC in the past, but now appears very important in the natural history of this cancer. This review is an EOC immunology state of art and focuses on the place of immunotherapy in future. A systematic review of published studies was performed. Medline baseline interrogation was performed with the following keywords: "Ovarian carinoma, immunotherapy, T-lymphocyte, regulator T-lymphocyte, dendritic cells, macrophage, antigen, chemotherapy, surgery, clinical trials". Identified publications (English or French) were assessed for the understanding of EOC immunology and the place of conventional treatment and immunotherapy strategy. Intratumoral infiltration by immune cells is a strong prognotic factor in EOC. Surgery and chemotherapy in EOC decrease imunosuppression in patients. The antitumoral immunity is a part of the therapeutic action of surgery and chemotherapy. Until now, immunotherapy gave some disappointing results, but the new drugs that target the tolerogenic tumoral microenvironnement rise and give a new hope in the treatment of cancer. Immunology controls the EOC natural history. The modulation of immunosuppressive microenvironment associated with the stimulation of antitumoral immunity could be the next revolution in the treatment of cancer. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
Neurogenesis as a new target for the development of antidepressant drugs.

PubMed

Pascual-Brazo, Jesus; Baekelandt, Veerle; Encinas, Juan Manuel

2014-01-01

Thirteen years have passed since the neurogenic hypothesis of depression was postulated. One of its aspects, that decreased neurogenesis could be causative of the onset of depression has been difficult to prove. Another aspect, the prediction that increasing neurogenesis would not only be supportive but also required to produce clinical results by antidepressants has gathered experimental validation. Thus a question arises: should new antidepressant strategies based solely on increasing neurogenesis be pursued? At the risk of disappointing the audience, we will not provide a straight answer to this question in this review, but we do hope to enlighten the reader regarding what is known about adult hippocampal neurogenesis, the indications and evidence of its involvement in the onset and treatment of depression, and the advances that have been made in the field in recent years. As we will recount here, the main body of support in favor of the neurogenic hypothesis of depression is based more on intimation than actual proof. However the rare examples that provide support are sufficiently robust to justify investment of resources and effort to clarify the issue, even if the involvement of neurogenesis, both in the etiology and the treatment of depression, is only partial and comprises only subtle components of this complex mental disorder.

Pharmacological therapy of spondyloarthritis.

PubMed

Palazzi, Carlo; D'Angelo, Salvatore; Gilio, Michele; Leccese, Pietro; Padula, Angela; Olivieri, Ignazio

2015-01-01

The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs. A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account. Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.
Should body weight-supported treadmill training and robotic-assistive steppers for locomotor training trot back to the starting gate?

PubMed

Dobkin, Bruce H; Duncan, Pamela W

2012-05-01

Body weight-supported treadmill training (BWSTT) and robotic-assisted step training (RAST) have not, so far, led to better outcomes than a comparable dose of progressive over-ground training (OGT) for disabled persons with stroke, spinal cord injury, multiple sclerosis, Parkinson's disease, or cerebral palsy. The conceptual bases for these promising rehabilitation interventions had once seemed quite plausible, but the results of well-designed, randomized clinical trials have been disappointing. The authors reassess the underpinning concepts for BWSTT and RAST, which were derived from mammalian studies of treadmill-induced hind-limb stepping associated with central pattern generation after low thoracic spinal cord transection, as well as human studies of the triple crown icons of task-oriented locomotor training, massed practice, and activity-induced neuroplasticity. The authors retrospectively consider where theory and practice may have fallen short in the pilot studies that aimed to produce thoroughbred interventions. Based on these shortcomings, the authors move forward with recommendations for the future development of workhorse interventions for walking. In the absence of evidence for physical therapists to employ these strategies, however, BWSTT and RAST should not be provided routinely to disabled, vulnerable persons in place of OGT outside of a scientifically conducted efficacy trial.
Developmental potential of elongating and elongated spermatids obtained after in-vitro maturation of isolated round spermatids.

PubMed

Cremades, N; Sousa, M; Bernabeu, R; Barros, A

2001-09-01

Round spermatid injections are associated with disappointing clinical outcomes, and although these cells have been shown to mature into late spermatids in vitro, the developmental potential of such gametes remains to be demonstrated. Round spermatids were isolated from 12 testicle samples of patients with obstructive azoospermia, hypoplasia, complete maturation arrest, and incomplete Sertoli cell-only syndrome. They were cultured for 7 days at 32 degrees C, 5% CO(2)in air, in microdrops of Vero cell-conditioned medium containing 10% synthetic serum substitute. From the 238 round spermatids cultured, 25.2% attained the elongating and 5.5% the elongated spermatid stage (3-4 days per step). Relatively higher maturation rates were found in cases with obstructive azoospermia, but differences were significant only for elongated spermatids (9.3%). No differences were found in maturation rates between cases with non-obstructive azoospermia (4.3% of elongated spermatids). Experimental microinjections with elongating and elongated spermatids revealed a low fertilization rate (40.9%) but a normal blastocyst formation rate (60%). Late spermatids resulting from in-vitro culture of round spermatids in conditioned medium, either in controls in cases with a spermiogenetic block, appeared able to successfully fertilize the human oocyte and elicit normal embryo development.
Spatial and Temporal Coordination of Bone Marrow-Derived Cell Activity During Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications

PubMed Central

Meisner, Joshua K.; Price, Richard J.

2010-01-01

Arterial occlusive disease (AOD) is the leading cause of morbidity and mortality through the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating AOD has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here we present the evidence suggesting roles for multiple BMC populations from neutrophils and mast cells to progenitor cells and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development. PMID:21044213
A Grounded theory study of the intention of nurses to leave the profession 1

PubMed Central

Alilu, Leyla; Zamanzadeh, Vahid; Valizadeh, Leila; Habibzadeh, Hosein; Gillespie, Mark

2017-01-01

ABSTRACT Objective: this study explores the process of the development of an intention to leave bedside nursing. Method: the process was studied from the perspective of 21 nurses using the grounded theory method. Data were collected using semi-structured interviews and the constant comparative method of Corbin and Strauss was used for data analysis. Results: according to the participants, the two main categories, "social image of nursing", and "culture and structure of the bedside", were the contextual factors that influence why nurses are leaving bedside care provision. Disappointment with a perceived lack of progress or improvement in the clinical experience formed primary psychosocial concerns for the participants. Competence and a process of self-control were steps taken by the participants. These, associated with interventional conditions produced the outcomes of the loss of professional commitment and desire to leave bedside nursing. "Failure to integrate personal expectations with organizational expectations: in search of escape" was the central category of the study that linked the categories together. Conclusion: the findings of this study provide useful information about the needs of nurses for overcoming the intention to leave bedside care. The identification of this process can help in recognizing emerging problems and providing solutions for them. PMID:28591301
Alzheimer's disease prevention: from risk factors to early intervention.

PubMed

Crous-Bou, Marta; Minguillón, Carolina; Gramunt, Nina; Molinuevo, José Luis

2017-09-12

Due to the progressive aging of the population, Alzheimer's disease (AD) is becoming a healthcare burden of epidemic proportions for which there is currently no cure. Disappointing results from clinical trials performed in mild-moderate AD dementia combined with clear epidemiological evidence on AD risk factors are contributing to the development of primary prevention initiatives. In addition, the characterization of the long asymptomatic stage of AD is allowing the development of intervention studies and secondary prevention programmes on asymptomatic at-risk individuals, before substantial irreversible neuronal dysfunction and loss have occurred, an approach that emerges as highly relevant.In this manuscript, we review current strategies for AD prevention, from primary prevention strategies based on identifying risk factors and risk reduction, to secondary prevention initiatives based on the early detection of the pathophysiological hallmarks and intervention at the preclinical stage of the disease. Firstly, we summarize the evidence on several AD risk factors, which are the rationale for the establishment of primary prevention programmes as well as revising current primary prevention strategies. Secondly, we review the development of public-private partnerships for disease prevention that aim to characterize the AD continuum as well as serving as platforms for secondary prevention trials. Finally, we summarize currently ongoing clinical trials recruiting participants with preclinical AD or a higher risk for the onset of AD-related cognitive impairment.The growing body of research on the risk factors for AD and its preclinical stage is favouring the development of AD prevention programmes that, by delaying the onset of Alzheimer's dementia for only a few years, would have a huge impact on public health.
A dismantling study of assertive outreach services: comparing activity and outcomes following replacement with the FACT model.

PubMed

Firn, Mike; Hindhaugh, Keelyjo; Hubbeling, Dieneke; Davies, Gwyn; Jones, Ben; White, Sarah Jane

2013-06-01

Financial constraints and some disappointing research evaluations have seen English assertive outreach (AO) teams subject to remodelling, decommissioning and integration into standard care. We tested a specific alternative model of integrating the AO function from two AO teams into six standard community mental health teams (CMHT). The Flexible Assertive Community Treatment model (FACT) was adopted from the Netherlands (Van Veldhuizen, Commun Mental Health J 43(4):421-433, 2007; Bond and Drake, Commun Mental Health J 43(4):435-438, 2007). We aimed to demonstrate non-inferiority in clinical effectiveness and thereby show cost efficiencies associated with FACT. Outcomes were compared in a mirror-image study of the 12 months periods pre- and post-service change with eligible individuals from the AO teams' caseloads (n = 112) acting as their own controls. We also conducted a cost-consequence analysis of the changes. Outcome data regarding admissions, use of crisis and home treatment, frequency of contact and DNA rate were extracted from the electronic patient record. The results show AO patients (n = 112) transferred to standard CMHTs with FACT had significantly fewer admissions and a halving of bed use (21 fewer admission and 2,394 fewer occupied bed days) whilst being in receipt of a less intensive service (2,979 fewer contacts). This was offset by significantly poorer engagement but not by increased use of crisis and home treatment services. Enhancing multi-disciplinary CMHTs with FACT provides a clinically effective alternative to AO teams. FACT offers a cost-effective model compared to AO.
Thinking outside the Box: Rotor Modulation in the Treatment of Atrial Fibrillation.

PubMed

Sehra, Ruchir; Narayan, Sanjiv M; Hummel, John

2013-01-01

Ablation for atrial fibrillation (AF) is an important and exciting therapy whose results remain suboptimal. Although most clinical trials show that ablation eliminates AF more effectively than medications, it is disappointing that the continued single procedural success remains ≈50% despite the substantial advances that have taken place in imaging, catheter positioning and energy delivery. Focal impulse and rotor modulation (FIRM), on the other hand, offers the opportunity to precisely define and then ablate patient-specific sustaining mechanisms for AF, rather than trying to eliminate all possible AF triggers. For over a decade, electrophysiologists have described cases in which AF terminates after only limited ablation - usually that cannot be explained by 'random' meandering wavelets. Indeed, recent studies from several laboratories show that all forms of clinical AF are typically 'driven' by stable electrical rotors and focal sources, not by multiple meandering waves. FIRM mapping enables an operator to place a catheter at typically 1-3 predicted sites in the atria, and with <5-10 minutes of RF ablation, terminate AF and potentially render it non-inducible. Several independent laboratories have now shown that such FIRM ablation alone can terminate or substantially slow AF in >80% of patients with persistent and paroxysmal AF and increase the single procedure rate of AF elimination from 50% with PV isolation alone to >80%. Ongoing studies hint that FIRM only ablation, enabling ablation times in the range observed for typical atrial flutter, may also achieve these high success rates without subsequent trigger ablation. This review summarizes the current state-of-the-art on FIRM mapping and ablation.
Chronic activation of wild-type epidermal growth factor receptor and loss of Cdkn2a cause mouse glioblastoma formation.

PubMed

Acquaviva, Jaime; Jun, Hyun Jung; Lessard, Julie; Ruiz, Rolando; Zhu, Haihao; Donovan, Melissa; Woolfenden, Steve; Boskovitz, Abraham; Raval, Ami; Bronson, Roderick T; Pfannl, Rolf; Whittaker, Charles A; Housman, David E; Charest, Al

2011-12-01

Glioblastoma multiforme (GBM) is characterized by overexpression of epidermal growth factor receptor (EGFR) and loss of the tumor suppressors Ink4a/Arf. Efforts at modeling GBM using wild-type EGFR in mice have proven unsuccessful. Here, we present a unique mouse model of wild-type EGFR-driven gliomagenesis. We used a combination of somatic conditional overexpression and ligand-mediated chronic activation of EGFR in cooperation with Ink4a/Arf loss in the central nervous system of adult mice to generate tumors with the histopathologic and molecular characteristics of human GBMs. Sustained, ligand-mediated activation of EGFR was necessary for gliomagenesis, functionally substantiating the clinical observation that EGFR-positive GBMs from patients express EGFR ligands. To gain a better understanding of the clinically disappointing EGFR-targeted therapies for GBM, we investigated the molecular responses to EGFR tyrosine kinase inhibitor (TKI) treatment in this model. Gefitinib treatment of primary GBM cells resulted in a robust apoptotic response, partially conveyed by mitogen-activated protein kinase (MAPK) signaling attenuation and accompanied by BIM(EL) expression. In human GBMs, loss-of-function mutations in the tumor suppressor PTEN are a common occurrence. Elimination of PTEN expression in GBM cells posttumor formation did not confer resistance to TKI treatment, showing that PTEN status in our model is not predictive. Together, these findings offer important mechanistic insights into the genetic determinants of EGFR gliomagenesis and sensitivity to TKIs and provide a robust discovery platform to better understand the molecular events that are associated with predictive markers of TKI therapy.
Bench to bedside: the quest for quality in experimental stroke research.

PubMed

Dirnagl, Ulrich

2006-12-01

Over the past decades, great progress has been made in clinical as well as experimental stroke research. Disappointingly, however, hundreds of clinical trials testing neuroprotective agents have failed despite efficacy in experimental models. Recently, several systematic reviews have exposed a number of important deficits in the quality of preclinical stroke research. Many of the issues raised in these reviews are not specific to experimental stroke research, but apply to studies of animal models of disease in general. It is the aim of this article to review some quality-related sources of bias with a particular focus on experimental stroke research. Weaknesses discussed include, among others, low statistical power and hence reproducibility, defects in statistical analysis, lack of blinding and randomization, lack of quality-control mechanisms, deficiencies in reporting, and negative publication bias. Although quantitative evidence for quality problems at present is restricted to preclinical stroke research, to spur discussion and in the hope that they will be exposed to meta-analysis in the near future, I have also included some quality-related sources of bias, which have not been systematically studied. Importantly, these may be also relevant to mechanism-driven basic stroke research. I propose that by a number of rather simple measures reproducibility of experimental results, as well as the step from bench to bedside in stroke research may be made more successful. However, the ultimate proof for this has to await successful phase III stroke trials, which were built on basic research conforming to the criteria as put forward in this article.
Women know best--findings from a thematic analysis of 5,214 surveys of abortion care experience.

PubMed

McLemore, Monica R; Desai, Sheila; Freedman, Lori; James, Evelyn Angel; Taylor, Diana

2014-01-01

Patient experience is an essential component of quality care. Few studies have comprehensively evaluated patient experiences of abortion care. The objectives of this study were to describe women's experiences of abortion care in their own words, and to determine themes across patient experiences. Data for this thematic analysis, a qualitative method that allows for the identification, analysis, and report of patterns or themes within data, come from a larger study of safety and quality of aspiration abortion care across 22 clinical sites. Participants completed an abortion experience survey including fixed choice questions and an open-ended question: "Is there anything you would like to tell us about your experience?" The data were then categorized by responses to another survey question: "Overall, was your experience about, better, or worse than you expected?" A total of 5,214 responses were analyzed. Women reported positive abortion care experiences with the majority of women rating their experience as better than expected (n = 3,600). Two major themes that emerged from the data include clinic- and patient-level factors that impact how patients rate their experiences. Analysis of the responses categorized in the worse than expected group (n = 136) found that women primarily faulted clinic-level factors for their negative experiences, such as pain control and management, and wait time for appointments and in clinic. This analysis highlights specific areas of abortion care that influence patients' experience. The few women who were disappointed by care in the clinic tended to fault readily modifiable clinical factors, and provided suggested areas of improvement to enhance positive experiences related to their abortion care. Copyright © 2014 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.
Multidisciplinary analysis of Skylab photography for highway engineering purposes. [Maine

NASA Technical Reports Server (NTRS)

Stoeckeler, E. G.; Woodman, R. G. (Principal Investigator); Farrell, R. S.

1975-01-01

The author has identified the following significant results. The greatly increased resolution of ground features by Skylab as compared with LANDSAT is considered to be best in the S190B high resolution film, followed by S190A camera stations 4, 5, and 6 respectfully. Results of the study of vegetation damage sites using data derived from S190A film were disappointing. The major cause of detection problems is the graininess of the CIR film. Good results were achieved for the hydrology-land use study. Both camera systems gave better agreement with the ground truth than did LANDSAT imagery. Surficial geology and glacial landform areas were clearly visible in single scenes. Several previously unmapped or unknown features were detected, especially in eastern coastal Maine.
Enhanced performance of macrophage-encapsulated nanoparticle albumin-bound-paclitaxel in hypo-perfused cancer lesions

NASA Astrophysics Data System (ADS)

Leonard, Fransisca; Curtis, Louis T.; Yesantharao, Pooja; Tanei, Tomonori; Alexander, Jenolyn F.; Wu, Min; Lowengrub, John; Liu, Xuewu; Ferrari, Mauro; Yokoi, Kenji; Frieboes, Hermann B.; Godin, Biana

2016-06-01

Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver.Hypovascularization in tumors such as liver metastases originating from breast and other organs correlates with poor chemotherapeutic response and higher mortality. Poor prognosis is linked to impaired transport of both low- and high-molecular weight drugs into the lesions and to high washout rate. Nanoparticle albumin-bound-paclitaxel (nAb-PTX) has demonstrated benefits in clinical trials when compared to paclitaxel and docetaxel. However, its therapeutic efficacy for breast cancer liver metastasis is disappointing. As macrophages are the most abundant cells in the liver tumor microenvironment, we design a multistage system employing macrophages to deliver drugs into hypovascularized metastatic lesions, and perform in vitro, in vivo, and in silico evaluation. The system encapsulates nAb-PTX into nanoporous biocompatible and biodegradable multistage vectors (MSV), thus promoting nAb-PTX retention in macrophages. We develop a 3D in vitro model to simulate clinically observed hypo-perfused tumor lesions surrounded by macrophages. This model enables evaluation of nAb-PTX and MSV-nab PTX efficacy as a function of transport barriers. Addition of macrophages to this system significantly increases MSV-nAb-PTX efficacy, revealing the role of macrophages in drug transport. In the in vivo model, a significant increase in macrophage number, as compared to unaffected liver, is observed in mice, confirming the in vitro findings. Further, a mathematical model linking drug release and retention from macrophages is implemented to project MSV-nAb-PTX efficacy in a clinical setting. Based on macrophage presence detected via liver tumor imaging and biopsy, the proposed experimental/computational approach could enable prediction of MSV-nab PTX performance to treat metastatic cancer in the liver. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07796f
Videofluoroscopy in motor neurone disease prior to cricopharyngeal myotomy.

PubMed Central

Wilson, P. S.; Bruce-Lockhart, F. J.; Johnson, A. P.

1990-01-01

Cricopharyngeal myotomy is a recognised treatment for the dysphagia in motor neurone disease, although the results are sometimes disappointing. In this study, 27 patients with motor neurone disease causing significant dysphagia have been investigated by the technique of videofluoroscopy, in order to determine the nature of their swallowing disability; those patients found suitable have been offered cricopharyngeal myotomy. Of the 27 patients, only seven were found to have cricopharyngeal dysfunction as the predominant disability and, of these, six underwent myotomy, resulting in relief of dysphagia in five, three of whom returned to a near normal diet. Previous studies showed poor overall benefit from cricopharyngeal myotomy. Videofluoroscopy allows accurate patient selection, and a much improved outcome in the selected group. PMID:2241057
Reconstruction of Traumatic Defect of the Lower Third of the Leg Using a Combined Therapy: Negative Pressure Wound Therapy, Acellular Dermal Matrix, and Skin Graft

PubMed Central

Brongo, Sergio; Campitiello, Nicola; Rubino, Corrado

2014-01-01

The reconstruction of lower third of the leg is one of the most challenging problems for plastic and reconstructive surgeons and current approaches are still disappointing. We show an easy option to obtain a coverage of traumatic pretibial defects with good aesthetic and functional results: the association of negative pressure wound therapy, acellular dermal matrix, and skin graft. The choice of this combined therapy avoids other surgical procedures such as local perforator flaps and free flaps that require more operating time, special equipment, and adequate training. PMID:25177509
Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia

PubMed Central

Jabbour, Elias J.; Hughes, Timothy P.; Cortés, Jorge E.; Kantarjian, Hagop M.; Hochhaus, Andreas

2014-01-01

Despite vast improvements in treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment. PMID:24050507
Cancer Prevention by Tocopherols and Tea Polyphenols

PubMed Central

Yang, Chung S.; Li, Guangxun; Yang, Zhihong; Guan, Fei; Chen, Amber; Ju, Jihyeung

2013-01-01

Tocopherols (vitamin E) and tea polyphenols have been reported to have cancer preventive activities. Large-scale human trials with high doses of alpha-tocopherol, however, have produced disappointing results. This review presents data showing that γ- and δ-tocopherols inhibit colon, lung, mammary and prostate carcinogenesis in animal models, whereas α-tocopherol is ineffective in animal and human studies. Possible mechanisms of action are discussed. A broad cancer preventive activity of green tea polyphenols has been demonstrated in animal models, and many mechanisms have been proposed. The cancer preventive activity of green tea in humans, however, has not been conclusively demonstrated and remains to be further investigated. PMID:23403075
Vectorization efforts to increase Gram-negative intracellular drug concentration: a case study on HldE-K inhibitors.

PubMed

Atamanyuk, Dmytro; Faivre, Fabien; Oxoby, Mayalen; Ledoussal, Benoit; Drocourt, Elodie; Moreau, François; Gerusz, Vincent

2013-03-14

In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies.
Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia.

PubMed

Jabbour, Elias J; Hughes, Timothy P; Cortés, Jorge E; Kantarjian, Hagop M; Hochhaus, Andreas

2014-07-01

Despite vast improvements in the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment.
Creativity and mood disorders: The enigmatic case of Isaak Il'ich Levitan (1860-1900).

PubMed

Lerner, Vladimir; Margolin, Jacob; Witztum, Eliezer

2017-05-01

Isaak Levitan (1860-1900) was one of Russia's most influential landscape artists. He lived a very short life, only 40 years, but left more than 1000 paintings. He suffered from mood fluctuations, and died as a result of serious heart disease. After an introduction related to the issue of creativity and mental disorders, a short biography of Levitan's life is outlined, followed by some examples of his mood and behavior. A section on the mood's reflection in Levitan's professional work is followed by a description of his romantic loves and disappointments and his relationship with his contemporary Russian, the writer Anton Chekhov.

Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy.

PubMed

von Karstedt, Silvia; Montinaro, Antonella; Walczak, Henning

2017-05-24

The discovery that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of cancer cells without causing toxicity in mice has led to the in-depth study of pro-apoptotic TRAIL receptor (TRAIL-R) signalling and the development of biotherapeutic drug candidates that activate TRAIL-Rs. The outcome of clinical trials with these TRAIL-R agonists has, however, been disappointing so far. Recent evidence indicates that many cancers, in addition to being TRAIL resistant, use the endogenous TRAIL-TRAIL-R system to their own advantage. However, novel insight on two fronts - how resistance of cancer cells to TRAIL-based pro-apoptotic therapies might be overcome, and how the pro-tumorigenic effects of endogenous TRAIL might be countered - gives reasonable hope that the TRAIL system can be harnessed to treat cancer. In this Review we assess the status quo of our understanding of the biology of the TRAIL-TRAIL-R system - as well as the gaps therein - and discuss the opportunities and challenges in effectively targeting this pathway.
Listening to the student voice to improve educational software.

PubMed

van Wyk, Mari; van Ryneveld, Linda

2017-01-01

Academics often develop software for teaching and learning purposes with the best of intentions, only to be disappointed by the low acceptance rate of the software by their students once it is implemented. In this study, the focus is on software that was designed to enable veterinary students to record their clinical skills. A pilot of the software clearly showed that the program had not been received as well as had been anticipated, and therefore the researchers used a group interview and a questionnaire with closed-ended and open-ended questions to obtain the students' feedback. The open-ended questions were analysed with conceptual content analysis, and themes were identified. Students made valuable suggestions about what they regarded as important considerations when a new software program is introduced. The most important lesson learnt was that students cannot always predict their needs accurately if they are asked for input prior to the development of software. For that reason student input should be obtained on a continuous and regular basis throughout the design and development phases.
Ways of Hoping: Navigating the Paradox of Hope and Despair in Chronic Pain.

PubMed

Eaves, Emery R; Nichter, Mark; Ritenbaugh, Cheryl

2016-03-01

In this paper, we explore hope in the context of living with chronic pain. Individuals with chronic pain from temporomandibular disorder(s) were interviewed four to five times over the course of their 18-month participation in a clinical trial investigating the effectiveness of Traditional Chinese Medicine. We sought to understand shifts in participants' descriptions of expectations and hopefulness, particularly with regard to the work involved in counterbalancing positive thinking with buffers against disappointment. We found hope to be a dynamic and multifaceted mindset as distinct from being a single entity to be measured. Drawing upon Polanyi's concept of tacit knowing, we explore how different ways of hoping emerge and index one another in participant narratives. We offer a working typology of hope and raise as an issue the manner in which the paradox of hope--hoping enough to carry on while keeping hopes in check to avoid the ever-present possibility of despair--complicates simplistic notions of the relationship between positive thinking and the placebo response.
[History and progress of trachea transplantation in Mexico].

PubMed

Garrido-Cardona, Rubén E; Rico-Escobar, Edna; Barrera-Ramírez, Elisa

2015-01-01

Central airway obstruction and particularly tracheal stenosis is a clinical problem where definite resolution is a tracheal resection, evaluating the magnitude, length, and ventilatory compromise of patient. The resectable fragment is limited to 30% of the total length in children, or 6 cm in adults with terminal end anastomosis. The replacement of longer sections through allogeneic transplantation has been disappointing due to the unfeasibility of the organ, rejection of the graft, and the highly complicated surgical procedure. Tissue bioengineering has designed the replacement of functional organs generated in vitro in the short term, with the absence of immunological responses to the graft. This is based on a non-biological matrix where epithelial and mesenchymal cells are planted in such a matrix. In this document, we review the history and development of trachea transplantation in Mexico as well as the application of these new technologies in the context of its world development, which is a reality in other countries as a new alternative in obstructive illness of the airway.
Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases

PubMed Central

Aggarwal, Bharat B.; Sundaram, Chitra; Prasad, Seema; Kannappan, Ramaswamy

2010-01-01

Initially discovered in 1938 as a “fertility factor,” vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-κB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation. PMID:20696139
Simple Model for Identifying Critical Regions in Atrial Fibrillation

NASA Astrophysics Data System (ADS)

Christensen, Kim; Manani, Kishan A.; Peters, Nicholas S.

2015-01-01

Atrial fibrillation (AF) is the most common abnormal heart rhythm and the single biggest cause of stroke. Ablation, destroying regions of the atria, is applied largely empirically and can be curative but with a disappointing clinical success rate. We design a simple model of activation wave front propagation on an anisotropic structure mimicking the branching network of heart muscle cells. This integration of phenomenological dynamics and pertinent structure shows how AF emerges spontaneously when the transverse cell-to-cell coupling decreases, as occurs with age, beyond a threshold value. We identify critical regions responsible for the initiation and maintenance of AF, the ablation of which terminates AF. The simplicity of the model allows us to calculate analytically the risk of arrhythmia and express the threshold value of transversal cell-to-cell coupling as a function of the model parameters. This threshold value decreases with increasing refractory period by reducing the number of critical regions which can initiate and sustain microreentrant circuits. These biologically testable predictions might inform ablation therapies and arrhythmic risk assessment.
Hypnosis in the treatment of trauma: a promising, but not fully supported, efficacious intervention.

PubMed

Cardeña, E

2000-04-01

Hypnotic techniques for the treatment of posttraumatic conditions were often used by the clinical pioneers of the end of the 19th century and by military therapists treating soldiers during the 20th century's conflagrations. More recently, hypnosis has also been used with survivors of sexual assault, accidents, and other traumas, and with various groups, including children and ethnic minorities. Nonetheless, there have been almost no systematic studies on the efficacy of hypnosis for posttraumatic disorders. This state of affairs is especially disappointing considering that: hypnosis can be easily integrated into therapies that are commonly used with traumatized clients; a number of PTSD individuals have shown high hypnotizability in various studies; hypnosis can be used for symptoms associated with PTSD; and hypnosis may help modulate and integrate memories of trauma. Hypnotic techniques may indeed be efficacious for posttraumatic conditions, but systematic group or single-case studies need to be conducted before reaching that conclusion.
Considering Complex Objectives and Scarce Resources in Information Systems' Analysis.

ERIC Educational Resources Information Center

Crowther, Warren

The low efficacy of many of the library and large-scale information systems that have been implemented in the developing countries has been disappointing, and their appropriateness is often questioned in the governmental and educational institutions of more industrialized countries beset by budget-crunching and a very dynamic transformation of…
A Model for Managing Anger and Conflict.

ERIC Educational Resources Information Center

Hamilton, Beatrice

Anger is probably the most misunderstood and least expressed feeling. To understand anger, it is necessary to explore the process. Anger usually follows an experience of frustration, unmet expectations, loss of self-respect, and fear. The next stage seems to be anxiety, which may be interpreted as a disappointment, discomfort, or powerlessness.…
Why Union Activists Write Good Stories

ERIC Educational Resources Information Center

Worthen, Helena H.

2013-01-01

The representative structure of a union is a maze which, when travelled as a narrative, has drama at every turn. It sets up expectations, pits good against evil, involves many characters with different interests, keeps the clock ticking, and offers opportunities for happy endings (and disappointments) at every level. Union members who are not…
Empowered Positions? Listening to Sexually Experienced Young Women Talking about Sex, Disappointments, and Compromise

ERIC Educational Resources Information Center

Sieg, Ellen

2008-01-01

Purpose: This paper aims to discuss how sex and relationship education (SRE) could benefit from considering current levels of young women's empowerment in (hetero)sexual relationships and challenge popular notions of twenty-first century young women "having it all" and occupying powerful relational and sexual positions.…
The Character to Seek Justice: Showing Fairness to Diverse Visions of Character Education.

ERIC Educational Resources Information Center

Glanzer, Perry L.

1998-01-01

Alfie Kohn's article in the February 1997 "Kappan," which questioned the world views informing character education, was disappointing. His criticisms of habit formation were misdirected, and he failed to reconcile the various world views held by parents and children. Character, like other human endeavors, requires vigorous training in…
An Online, Interactive Renewable Energy Laboratory

ERIC Educational Resources Information Center

O'Leary, D. A.; Shattuck, J.; Kubby, J.

2012-01-01

An undergraduate introductory science, technology, engineering, and math (STEM) class can be a jarring disappointment to new students expecting to work with cutting-edge, real-world technology. Their cell phones are often more technically advanced and real-world than the tools used in a class lab. Not surprisingly, many complain that the STEM labs…
Effects of Reactive and Nonreactive Toys on the Vocalizations of Toddlers with Down Syndrome.

ERIC Educational Resources Information Center

Smith, Shannon J.; Neeley, Richard A.; Clymer, Debbie P.; Justen, Joseph E., III

2001-01-01

Four toddlers with Down syndrome (ages 10-30 months) were presented with six nonreactive and reactive toys for 90 sessions of free play. When the toys were nonreactive, the subjects vocalized to express their disappointment or to seek assistance from the adults in the room. (Contains references.) (Author/CR)
Striving toward Openness: But What Do We Really Mean?

ERIC Educational Resources Information Center

Rolfe, Vivien

2017-01-01

The global open education movement is striving toward openness as a feature of academic policy and practice, but evidence shows that these ambitions are far from mainstream, and levels of awareness in institutions is often disappointingly low. Those advocating for open education are seeking to widen engagement, but how targeted and persuasive are…
Juanita Fights the School Board.

ERIC Educational Resources Information Center

Velasquez, Gloria

This book relates the fictional story of Juanita Chavez, a Mexican-American teenager who unjustly faces expulsion from school after fighting with a White student who was spreading rumors about her family. Juanita knows that if she is expelled this will greatly disappoint her parents and shatter her dream of becoming the first one in her family to…
Homework Emotion Management at the Secondary School Level: Antecedents and Homework Completion

ERIC Educational Resources Information Center

Xu, Jianzhong

2011-01-01

Background/Context: For many children, doing homework becomes an emotionally charged event and one of the most disappointing aspects of school life. It is surprising to note, however, that homework emotion management is noticeably absent from much contemporary homework literature. Purpose: The primary propose of the present study was to propose…
Five Perspectives for Leadership Success

ERIC Educational Resources Information Center

Toll, Cathy A.

2017-01-01

New school leaders typically start out with enthusiasm--but sometime in their first year, they often find themselves disappointed, exhausted, and full of self-doubt. In this article, Cathy A. Toll discusses five perspectives that helped her enthusiasm for the job when she was a new school leader: (1) Teachers are well-intentioned, hard-working…
The Effects of Computerized Instruction and Systematic Presentation and Review of Math Fact Acquisition and Fluency

ERIC Educational Resources Information Center

Reynolds, Jennifer L.

2010-01-01

Cross country investigations have repeatedly demonstrated the disappointing math performance of students in the United States (Beatty, 1997; Ferrini-Mundy & Schmidt, 2005). The National Council of Teachers of Mathematics (2000) listed failure to rapidly recall basic facts as a common problem associated with disabilities in mathematics and…
Measuring Teachers' Contributions to Student Learning Growth for Nontested Grades and Subjects. Research & Policy Brief

ERIC Educational Resources Information Center

Goe, Laura; Holdheide, Lynn

2011-01-01

The growing need for more information about measuring teachers' contributions to student learning growth, particularly in nontested subjects and grades, is the impetus for this Research & Policy Brief. Although the research base in this area is disappointingly limited, the brief includes considerations and suggestions based on current models…

Cone Analysis of Southern Pines - A Guidebook

Treesearch

D.L. Bramlett; E.W. Belcher; G.L. DeBarr; G.D. Hertel; Robert P. Karrfalt; C.W. Lantz; T. Miller; K.D. Ware; H.O. Yates

1977-01-01

Southern pine tree improvement programs require an ample supply of improved seeds, but productron from southern pine seed orchards has often been disappointing. If high productron is to be malntained yields must be monitored and causes of seed losses must be identified. Techniques for determining seed efficiency were first used for red pine, Pinus resinosa...
Why Youth Mentoring Relationships End. Research in Action. Issue 5

ERIC Educational Resources Information Center

Spencer, Renee

2007-01-01

Recognizing that some early endings are unavoidable, the author maintains that many mentor-mentee relationships quickly dissolve due to factors that may be avoidable, such as disappointment and dissatisfaction with the relationship. Findings from a range of research studies are offered. Higher levels of program support may be required for matches…
Waiting for the Change: A Long and Disappointing Search for Multiculturalism and Inclusion

ERIC Educational Resources Information Center

Algozzine, Bob

2015-01-01

Inclusion or providing educational opportunities for all students alongside their natural neighbors and peers remains a highly valued goal for me. Ensuring that effective educational practices are available and provided to all students and that no cultural, ethnic, or other groups are disproportionately placed in ineffective education settings…
When Friends Disappoint: Boys' and Girls' Responses to Transgressions of Friendship Expectations

ERIC Educational Resources Information Center

MacEvoy, Julie Paquette; Asher, Steven R.

2012-01-01

In this study, the prevailing view that girls are pervasively more skilled in their friendships than boys was challenged by examining whether girls respond more negatively than boys when a friend violates core friendship expectations. Fourth- and fifth-grade children (n = 267) responded to vignettes depicting transgressions involving a friend's…
Instructional Choices in Language Arts: Reality or Illusion.

ERIC Educational Resources Information Center

Hensley, Robin

A first-year first grade teacher's professional disappointments were broken down into three divisions: (1) power and control, or the lack of them; (2) co-worker socialization; and (3) lack of professionalism and support. Lack of control was reflected in pressure from administrators to use certain texts, or even to decorate classrooms in a certain…
Perspectives of General and Special Educators on Fostering Self-Determination in Elementary and Middle Schools

ERIC Educational Resources Information Center

Stang, Kristin K.; Carter, Erik W.; Lane, Kathleen Lynne; Pierson, Melinda R.

2009-01-01

Recognizing that many youth with disabilities lack critical self-determination skills and that such deficits may be a contributing factor to disappointing postschool outcomes, educators and researchers have called for increased attention to promoting student self-determination in the early grades. The authors queried 891 elementary and middle…
Engineering as a Life-Long Career: Its Meaning, Its Satisfactions, Its Difficulties.

DTIC Science & Technology

1982-11-01

reached their career heights, are least likely of any group to be disappointed with their career success . It is Group 2 who evaluate their careers most...period, particularly if they do so relatively early, are most likely to reorient towards work, and most optimistic about their career success . These
ICT Reform Initiatives in Singapore Schools: A Complexity Theory Perspective

ERIC Educational Resources Information Center

Toh, Yancy; So, Hyo-Jeong

2011-01-01

The past two decades have witnessed an exponential growth in the use of technology in our daily life. Notwithstanding its phenomenal influence, the use of technology in education remains sporadic and disjointed. The promise that technology will bring deep-seated changes in the way that educators teach and students learn remains, disappointedly,…
The Disappointing Gift: Dispositional and Situational Moderators of Emotional Expressions

ERIC Educational Resources Information Center

Tobin, Renee M.; Graziano, William G.

2011-01-01

Inferences about emotions in children are limited by studies that rely on only one research method. Convergence across methods provides a stronger basis for inference by identifying method variance. This multimethod study of 116 children (mean age = 8.21 years) examined emotional displays during social exchange. Each child received a desirable…
From Pedagogically Relevant Corpora to Authentic Language Learning Contents

ERIC Educational Resources Information Center

Braun, Sabine

2005-01-01

The potential of corpora for language learning and teaching has been widely acknowledged and their ready availability on the Web has facilitated access for a broad range of users, including language teachers and learners. However, the integration of corpora into general language learning and teaching practice has so far been disappointing. In this…
Kant's Contribution to Moral Education: The Relevance of Catechistics

ERIC Educational Resources Information Center

Surprenant, Chris W.

2010-01-01

Kant's deontological ethics, along with Aristotle's virtue ethics and Mill's utilitarian ethics, is often identified as one of the three primary moral options between which individuals can choose. Given the importance of Kant's moral philosophy, it is surprising and disappointing how little has been written on his important contributions to moral…
What Can This Student Teach You about the Classroom?

ERIC Educational Resources Information Center

Shah, Nirvi

2009-01-01

This article profiles Tranette Myrthil, a student at Miami Edison Senior High School, which serves the Miami's Little Haiti neighborhood, one of the poorest communities in Florida. Tranette was always smarter than the curriculum allowed her to be. Now she is showing future teachers how to keep students engaged. Driven by her disappointment--and…
"Families' Perspectives on Interdisciplinary Professional Communication in Addressing Lifeplanning of Children with Special Health Care Needs"

ERIC Educational Resources Information Center

Rader, Rick A.; Kopetz, Patricia B.; Carter, Pamala J.

2001-01-01

Current research/literature identifies key, critical concerns of families with children who have special health care needs (ASHCAN). Emphasized are their expressed disappointments with overall transactional care between and among professionals helping their child(ren). Researchers of this study wanted to determine and evaluate the desires and…
The Role of Trust in Reflective Practice

ERIC Educational Resources Information Center

Benade, Leon

2018-01-01

Trust, as a philosophical concept in education, seems largely taken for granted, either because it is embedded in other discourses, or is self-evidently assumed to be one on which there is general agreement and understanding. Its associated notions, such as confidence and belief, have counters in such concepts as disappointment and betrayal. These…
State Treasure

ERIC Educational Resources Information Center

Olson, Cathy Applefeld

2013-01-01

When a music teacher is named Teacher of the Year for an entire state, one just know a special story awaits. The narrative of Heidi Welch, director of music at Hillsboro-Deering High School in New Hampshire, does not disappoint. Welch, who grew up in abject poverty and was often homeless, developed her love of music through memorizing and singing…
Average Revisited in Context

ERIC Educational Resources Information Center

Watson, Jane; Chick, Helen

2012-01-01

This paper analyses the responses of 247 middle school students to items requiring the concept of average in three different contexts: a city's weather reported in maximum daily temperature, the number of children in a family, and the price of houses. The mixed but overall disappointing performance on the six items in the three contexts indicates…
Inductive Discipline, Parental Expression of Disappointed Expectations, and Moral Identity in Adolescence

ERIC Educational Resources Information Center

Patrick, Renee B.; Gibbs, John C.

2012-01-01

Within the fields of socialization and moral development, the relationship of parenting to adolescents' sense of morality and self has been understudied. This study investigated the relationships between perceived parental disciplinary techniques and moral identity among early and middle adolescents. Participants included 93 (54% female) 5th, 8th…
Studying Visual Displays: How to Instructionally Support Learning

ERIC Educational Resources Information Center

Renkl, Alexander; Scheiter, Katharina

2017-01-01

Visual displays are very frequently used in learning materials. Although visual displays have great potential to foster learning, they also pose substantial demands on learners so that the actual learning outcomes are often disappointing. In this article, we pursue three main goals. First, we identify the main difficulties that learners have when…
Schools: The Evidence on Academies, Resources and Pupil Performance. Paper No. EA023

ERIC Educational Resources Information Center

McNally, Sandra

2015-01-01

England's performance in international tests of student achievement continues to be disappointing. Further improvement is essential not only for students' themselves but also for economic growth. This briefing considers the impact of Academies, school spending and teacher quality. Research evidence suggests that it is right to protect school…
Courtside: Gifted Irony?

ERIC Educational Resources Information Center

Zirkel, Perry A.

2005-01-01

During the 2002-03 school year, Michael B., Rebecca D., and Aldo V. were eighth-graders at the Regional Gifted Center program at the Beaubien School in the Chicago school system. In February, the Beaubien School held an annual contest for eighth-graders to determine the design for the class T-shirt. Michael was disappointed that his design did not…

AAHPERD 1986-2009: A Retrospective

ERIC Educational Resources Information Center

Landwer, Jerry E.

2009-01-01

The history of AAHPERD is important for understanding "who" we are and the chronology of events that brought us to this point in time. In its history, the Alliance has experienced many successes, many challenges, and a few disappointments. Some of these are chronicled in this article. A brief recounting of the past 25 years is given in…
Identifying Elementary School Student Opinion Leaders for Engagement in Evidence-Based Program Adaptation and Implementation

ERIC Educational Resources Information Center

Reiger, Christopher J.; Gibson, Jennifer E.; Passarelli, Rebecca E.; Flaspohler, Paul D.

2017-01-01

Evidence-based programs, such as bullying prevention, often demonstrate disappointing outcomes when widely disseminated. Engaging opinion leaders--those individuals whom others emulate and go to for advice--in the process of adaptation and implementation may improve outcomes. However, opinion leaders have the most influence on individuals who are…
Digital Literacy in the Marketing Curriculum: Are Female College Students Prepared for Digital Jobs?

ERIC Educational Resources Information Center

Mishra, Karen E.; Wilder, Kelly; Mishra, Aneil K.

2017-01-01

Employers seeking to capitalize on current marketing graduates' technological savvy may find a disappointing gap between their expectations and students' digital preparedness. This study examines these issues by investigating female students' attitudes and expectations with regard to using digital tools in marketing coursework and in a future…
Youth Tobacco Sales-to-Minors and Possession-Use-Purchase Laws: A Public Health Controversy

ERIC Educational Resources Information Center

Jason, Leonard A.; Pokorny, Steven B.; Muldowney, Kathleen; Velez, Melissa

2005-01-01

Tobacco use among youth remains one of our nation's most significant public health problems, and yet available evidence from prevention and cessation person-centered approaches has been mixed. Given these disappointing outcomes, some have recommended more public health approaches, and these include tobacco sales-to-minors and…
Understanding Teachers' Reluctance to the Pedagogical Use of ICT in the 1:1 Classroom

ERIC Educational Resources Information Center

Tallvid, Martin

2016-01-01

During the last decade, several "one laptop per student-initiatives" (1:1) have emerged as a solution to the recurrent disappointments with the pace of transformation of teaching methods in schools. However, an increasing number of research studies indicates, that despite major expenditure, increased access and improved technical…
What nurses want. Different generations. Different expectations.

PubMed

Greene, Jan

2005-03-01

Younger nurses have different career expectations than their older colleagues. They seek a balanced lifestyle with reasonable work hours, demand to use the latest technology and expect to be vocal members of the care team. If a hospital disappoints, they are quick to change jobs. How do you accommodate them without alienating veteran staff members?
The Case for Dreaming Big

ERIC Educational Resources Information Center

Domina, Thurston; Conley, AnneMarie; Farkas, George

2011-01-01

The American educational system is no fairy tale. Students who think that it takes nothing more than a wish upon a star to make their educational dreams come true are sure to be disappointed. The authors agree with Professor Rosenbaum: In order to realize their educational dreams, students must invest considerable effort. Rather than encouraging…
Mourning a Lost Childhood: A Therapeutic Task.

ERIC Educational Resources Information Center

Kulish, Nancy Mann

J. M. Barrie's popular story of Peter Pan depicts the never-neverland of an endless happy childhood. Analysis of the story and of J. M. Barrie's personal background, however, reveals that the tale is a conflicted solution to and separation from early childhood losses and disappointments. Themes of separation and reunion, redesertion and revenge…
Exposing the Glosses in Seligman and Fowler's (2011) Straw-Man Arguments

ERIC Educational Resources Information Center

Dyckman, John

2011-01-01

The author was disappointed to see an entire special issue of the "American Psychologist" (January 2011) devoted to military psychology, but he was especially concerned about the one-sided moral justifications presented by Seligman and Fowler (2011) in the final article of the issue. The author feels they misrepresented potential objections to…
Display Rule Application in a Disappointing Situation and Children's Emotional Reactivity: Relations with Social Competence.

ERIC Educational Resources Information Center

McDowell, David J.; O'Neil, Robin; Parke, Ross D.

2000-01-01

Examined associations among emotion display rule use, negative emotional reactivity, and fourth-graders' social competence. Found negative relation between self-reported negative emotional coping strategies and observed measures of display rule use. Found children who reported using more effective coping strategies for managing negative emotions…
The role of expectations, hype and ethics in neuroimaging and neuromodulation futures

PubMed Central

Rusconi, Elena; Mitchener-Nissen, Timothy

2014-01-01

The production of expectations or future-goals for the development of techniques which “read” and modulate brain function, represent an important practical tool for neuroscientists. These visions-of-the-future assist scientists by providing focus for both individual and cross-disciplinary research programs; they encourage the development of new industrial sectors, are used to justify the allocation of government resources and funding, and via the media can help capture the imagination and support of the public. However, such expectations need to be tempered by reality. Over-hyping brain imaging and modulation will lead to disappointment; disappointment that in turn can undermine its potential. Similarly, if neuroscientists focus their attention narrowly on the science without concomitant consideration of its future ethical, legal and social implications, then their expectations may remain unrealized. To develop these arguments herein we introduce the theoretical concept of expectations and the practical consequences of expectations. We contextualize these reflections by referring to brain imaging and modulation studies on deception, which encompass the measurement-suppression-augmentation range. PMID:25400557
Employment status and mortality in the context of high and low regional unemployment levels in Belgium (2001-2011): A test of the social norm hypothesis across educational levels.

PubMed

De Moortel, Deborah; Hagedoorn, Paulien; Vanroelen, Christophe; Gadeyne, Sylvie

2018-01-01

Because of compositional effects (more highly educated unemployed) and differences in the vulnerability towards the health consequences of unemployment (i.e. disappointment paradox hypothesis and/or status inconsistency for highly educated unemployed), it is argued that indicators of educational attainment need to be included when investigating the social norm of unemployment. Data from the 2001 census linked to register data from 2001-2011 are used, selecting all Belgian employed and unemployed between 30 and 59-year-old at time of the census. Poisson multilevel modelling was used to account for clustering of respondents within sub-districts. For individuals with low education levels, the relative difference in mortality rate ratios between the unemployed and employed is smallest in those regions where aggregate unemployment levels are high. For highly educated, this social norm effect was not found. This study suggest that the social norm effect is stronger for workers with low education levels, while highly educated workers suffer from disappointment and status inconsistency.
Employment status and mortality in the context of high and low regional unemployment levels in Belgium (2001–2011): A test of the social norm hypothesis across educational levels

PubMed Central

Hagedoorn, Paulien; Vanroelen, Christophe; Gadeyne, Sylvie

2018-01-01

Because of compositional effects (more highly educated unemployed) and differences in the vulnerability towards the health consequences of unemployment (i.e. disappointment paradox hypothesis and/or status inconsistency for highly educated unemployed), it is argued that indicators of educational attainment need to be included when investigating the social norm of unemployment. Data from the 2001 census linked to register data from 2001–2011 are used, selecting all Belgian employed and unemployed between 30 and 59-year-old at time of the census. Poisson multilevel modelling was used to account for clustering of respondents within sub-districts. For individuals with low education levels, the relative difference in mortality rate ratios between the unemployed and employed is smallest in those regions where aggregate unemployment levels are high. For highly educated, this social norm effect was not found. This study suggest that the social norm effect is stronger for workers with low education levels, while highly educated workers suffer from disappointment and status inconsistency. PMID:29420646
The role of executive functions and theory of mind in children's prosocial lie-telling.

PubMed

Williams, Shanna; Moore, Kelsey; Crossman, Angela M; Talwar, Victoria

2016-01-01

Children's prosocial lying was examined in relation to executive functioning skills and theory of mind development. Prosocial lying was observed using a disappointing gift paradigm. Of the 79 children (ages 6-12 years) who completed the disappointing gift paradigm, 47 (59.5%) told a prosocial lie to a research assistant about liking their prize. In addition, of those children who told prosocial lies, 25 (53.2%) maintained semantic leakage control during follow-up questioning, thereby demonstrating advanced lie-telling skills. When executive functioning was examined, children who told prosocial lies were found to have significantly higher performance on measures of working memory and inhibitory control. In addition, children who lied and maintained semantic leakage control also displayed more advanced theory of mind understanding. Although children's age was not a predictor of lie-telling behavior (i.e., truthful vs. lie-teller), age was a significant predictor of semantic leakage control, with older children being more likely to maintain their lies during follow-up questioning. Copyright © 2015 Elsevier Inc. All rights reserved.
Indolent peritoneal mesothelioma: PI3K-mTOR inhibitors as a novel therapeutic strategy

PubMed Central

Dolly, Saoirse O; Migali, Cristina; Tunariu, Nina; Della-Pepa, Chiara; Khakoo, Shelize; Hazell, Steve; de Bono, Johann S; Kaye, Stanley B; Banerjee, Susana

2017-01-01

Peritoneal mesothelioma (MPeM) is a scarce abdominal-pelvic malignancy that presents with non-specific features and exhibits a wide clinical spectrum from indolent to aggressive disease. Due to it being a rare entity, there is a lack of understanding of its molecular drivers. Most treatment data are from limited small studies or extrapolated from pleural mesothelioma. Standard treatment includes curative surgery or pemetrexed-platinum palliative chemotherapy. To date, the use of novel targeted agents has been disappointing. Described is the management of two young women with papillary peritoneal mesothelioma with widespread recurrence having received platinum-pemetrexed chemotherapy. Both patients obtained symptomatic and disease benefit with apitolisib, a dual phosphoinositide 3-kinase-mammalian target of rapamycin (PI3K-mTOR) inhibitor for subsequent relapses, with one patient having a partial response for almost 3 years. Both are alive and well 10–13 years from diagnosis. Conclusion These case presentations highlight a subgroup of rare MPeM that behave indolently that is compatible with long-term survival. This series identifies the use of targeted therapies with PI3K-mTOR-based inhibitors as a novel approach, warranting further clinical assessment. Development of prognostic biomarkers is essential to aid identify tumour aggressiveness, help stratify patients and facilitate treatment decisions. PMID:28761723
DNA vaccine against visceral leishmaniasis: a promising approach for prevention and control.

PubMed

Kumar, A; Samant, M

2016-05-01

The visceral leishmaniasis (VL) caused by Leishmania donovani parasite severely affects large populations in tropical and subtropical regions of the world. The arsenal of drugs available is limited, and resistance is common in clinical field isolates. Therefore, vaccines could be an important alternative for prevention against VL. Recently, some investigators advocated the protective efficacy of DNA vaccines, which induces the T cell-based immunity against VL. The vaccine antigens are selected as conserved in various Leishmania species and provide a viable strategy for DNA vaccine development. Our understanding for DNA vaccine development against VL is not enough and much technological advancement is required. Improved formulations and methods of delivery are required, which increase the uptake of DNA vaccine by cells; optimization of vaccine vectors/encoded antigens to augment and direct the host immune response in VL. Despite the many genes identified as vaccine candidates, the disappointing potency of the DNA vaccines in VL underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the design, strategy, safety issues, varied candidates, progress and challenges that play a role in their ability against VL. © 2016 John Wiley & Sons Ltd.
A review of malaria vaccine clinical projects based on the WHO rainbow table

PubMed Central

2012-01-01

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below. PMID:22230255
Changing the course of pancreatic cancer--Focus on recent translational advances.

PubMed

Javle, Milind; Golan, Talia; Maitra, Anirban

2016-03-01

In the past decade, insightful preclinical research has led to important breakthroughs in our understanding of pancreatic cancer. Even though the vast majority of pancreatic cancers are KRAS mutated, not all pancreatic cancer tumors are "KRAS equal"; there seems to be varying dependencies on the KRAS pathway. While KRAS-targeting therapies have been disappointing in the clinic, 'synthetic lethal' approaches hold promise in this setting. The pancreatic cancer stromal microenvironment appears to have contradictory roles. While there is evidence to suggest that stromal barrier prevents drug delivery, in other circumstances, stroma can play a protective role and its disruption enhances tumor dissemination. Clinical trials aimed at manipulating the various stromal components are in progress. BRCA mutation-related pancreatic tumors illustrate a unique subtype with enhanced susceptibility to DNA damaging agents and PARP-inhibition. DNA repair defects in cancer extend beyond germ line BRCA mutation and may extend the indications for DNA repair-targeting agents. Immune strategies are an area of active investigation in pancreatic cancer. Although the initial trials of single-agent checkpoint inhibitors have been negative, combinational approaches using immune-modifying agents and vaccines appear promising and goal is to identify an 'immune-therapy responsive' profile in pancreatic cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.
The small chill: mild hypothermia for cardioprotection?

PubMed

Tissier, Renaud; Chenoune, Mourad; Ghaleh, Bijan; Cohen, Michael V; Downey, James M; Berdeaux, Alain

2010-12-01

Reducing the heart's temperature by 2-5°C is a potent cardioprotective treatment in animal models of coronary artery occlusion. The anti-infarct benefit depends upon the target temperature and the time at which cooling is instituted. Protection primarily results from cooling during the ischaemic period, whereas cooling during reperfusion or beyond offers little protection. In animal studies, protection is proportional to both the depth and duration of cooling. An optimal cooling protocol must appreciably shorten the normothermic ischaemic time to effectively salvage myocardium. Patients presenting with acute myocardial infarction could be candidates for mild hypothermia since the current door-to-balloon time is typically 90 min. But they would have to be cooled quickly shortly after their arrival. Several strategies have been proposed for ultra-fast cooling, but most like liquid ventilation and pericardial perfusion are too invasive. More feasible strategies might include cutaneous cooling, peritoneal lavage with cold solutions, and endovascular cooling with intravenous thermodes. This last option has been investigated clinically, but the results have been disappointing possibly because the devices lacked capacity to cool the patient quickly or cooling was not implemented soon enough. The mechanism of hypothermia's protection has been assumed to be energy conservation. However, whereas deep hypothermia clearly preserves ATP, mild hypothermia has only a modest effect on ATP depletion during ischaemia. Some evidence suggests that intracellular signalling pathways might be responsible for the protection. It is unknown how cooling could trigger these pathways, but, if true, then it might be possible to duplicate cooling's protection pharmacologically.
Physicians' degree of motivation regarding their perception of hypertension, and blood pressure control.

PubMed

Consoli, Silla M; Lemogne, Cédric; Levy, Alain; Pouchain, Denis; Laurent, Stephane

2010-06-01

Despite clear international guidelines, the achievement of blood pressure (BP) control is still disappointing. To determine whether physicians' perception of hypertension, in general, is related to their patients' BP measures. DUO-HTA is a French cross-sectional survey, which included a representative sample of 346 general practitioners, 209 cardiologists and 2014 hypertensive patients. Data were collected using two self-administered questionnaires filled out by the hypertensive patients and their physicians. A cluster analysis was performed on the responses given by the physicians, prior to the inclusion of their patients into the study, to 13 questions concerning their perception of hypertension. Physicians were divided into five groups, ranging from 'poorly motivated' to 'highly motivated' physicians, with regard to their perception of hypertension. More motivated physicians had a more confident and optimistic approach of hypertension, looked more empathetic and supportive towards patients and were characterized by higher rates of patients with controlled BP included into the study (range 32-42%, P=0.01 for trend). After adjusting for sociodemographic, clinical and psychological patient-related variables, separate analyses for the patients included into the survey by general practitioners or cardiologists found a significant decreasing gradient for SBP according to physicians' level of motivation (respectively, P=0.029 and P=0.021). Close results were observed in multivariate logistic regression analyses of uncontrolled hypertension. These results underline the importance of physicians' perception of hypertension, in addition or concurrently to their compliance with international guidelines, for a successful management of hypertensive patients

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