175 research outputs found

    Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

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    PURPOSE: Subsets of pituitary tumors exhibit an aggressive clinical courses and recur despite surgery, radiation, and chemotherapy. Because modulation of the immune response through inhibition of T-cell checkpoints has led to durable clinical responses in multiple malignancies, we explored whether pituitary adenomas express immune-related biomarkers that could suggest suitability for immunotherapy. Specifically, programmed death ligand 1 (PD-L1) has emerged as a potential biomarker whose expression may portend more favorable responses to immune checkpoint blockade therapies. We thus investigated the expression of PD-L1 in pituitary adenomas. METHODS: PD-L1 RNA and protein expression were evaluated in 48 pituitary tumors, including functioning and non-functioning adenomas as well as atypical and recurrent tumors. Tumor infiltrating lymphocyte populations were also assessed by immunohistochemistry. RESULTS: Pituitary tumors express variable levels of PD-L1 transcript and protein. PD-L1 RNA and protein expression were significantly increased in functioning (growth hormone and prolactin-expressing) pituitary adenomas compared to non-functioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary adenomas harbored higher levels of PD-L1 mRNA compared to recurrent tumors. Tumor infiltrating lymphocytes were observed in all pituitary tumors and were positively correlated with increased PD-L1 expression, particularly in the functional subtypes. CONCLUSIONS: Human pituitary adenomas harbor PD-L1 across subtypes, with significantly higher expression in functioning adenomas compared to non-functioning adenomas. This expression is accompanied by the presence of tumor infiltrating lymphocytes. These findings suggest the existence of an immune response to pituitary tumors and raise the possibility of considering checkpoint blockade immunotherapy in cases refractory to conventional management

    Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

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    Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

    A comprehensive study on the role of the Yersinia pestis virulence markers in an animal model of pneumonic plague

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    We determined the role of Yersinia pestis virulence markers in an animal model of pneumonic plague. Eleven strains of Y. pestis were characterized using PCR assays to detect the presence of known virulence genes both encoded by the three plasmids as well as chromosomal markers. The virulence of all Y. pestis strains was compared in a mouse model for pneumonic plague. The presence of all known virulence genes correlated completely with virulence in the Balb/c mouse model. Strains which lacked HmsF initially exhibited visible signs of disease whereas all other strains (except wild-type strains) did not exhibit any disease signs. Forty-eight hours post-infection, mice which had received HmsF– strains regained body mass and were able to control infection; those infected with strains possessing a full complement of virulence genes suffered from fatal disease. The bacterial loads observed in the lung and other tissues reflected the observed clinical signs as did the cytokine changes measured in these animals. We can conclude that all known virulence genes are required for the establishment of pneumonic plague in mammalian animal models, the role of HmsF being of particular importance in disease progression

    The role of conversation in health care interventions: enabling sensemaking and learning

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    <p>Abstract</p> <p>Background</p> <p>Those attempting to implement changes in health care settings often find that intervention efforts do not progress as expected. Unexpected outcomes are often attributed to variation and/or error in implementation processes. We argue that some unanticipated variation in intervention outcomes arises because unexpected conversations emerge during intervention attempts. The purpose of this paper is to discuss the role of conversation in shaping interventions and to explain why conversation is important in intervention efforts in health care organizations. We draw on literature from sociolinguistics and complex adaptive systems theory to create an interpretive framework and develop our theory. We use insights from a fourteen-year program of research, including both descriptive and intervention studies undertaken to understand and assist primary care practices in making sustainable changes. We enfold these literatures and these insights to articulate a common failure of overlooking the role of conversation in intervention success, and to develop a theoretical argument for the importance of paying attention to the role of conversation in health care interventions.</p> <p>Discussion</p> <p>Conversation between organizational members plays an important role in the success of interventions aimed at improving health care delivery. Conversation can facilitate intervention success because interventions often rely on new sensemaking and learning, and these are accomplished through conversation. Conversely, conversation can block the success of an intervention by inhibiting sensemaking and learning. Furthermore, the existing relationship contexts of an organization can influence these conversational possibilities. We argue that the likelihood of intervention success will increase if the role of conversation is considered in the intervention process.</p> <p>Summary</p> <p>The generation of productive conversation should be considered as one of the foundations of intervention efforts. We suggest that intervention facilitators consider the following actions as strategies for reducing the barriers that conversation can present and for using conversation to leverage improvement change: evaluate existing conversation and relationship systems, look for and leverage unexpected conversation, create time and space where conversation can unfold, use conversation to help people manage uncertainty, use conversation to help reorganize relationships, and build social interaction competence.</p

    Public Attitudes Towards Moral Enhancement. Evidence that Means Matter Morally

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    To gain insight into the reasons that the public may have for endorsing or eschewing pharmacological moral enhancement for themselves or for others, we used empirical tools to explore public attitudes towards these issues. Participants (N = 293) from the United States were recruited via Amazon’s Mechanical Turk and were randomly assigned to read one of several contrastive vignettes in which a 13-year-old child is described as bullying another student in school and then is offered an empathy-enhancing program. The empathy-enhancing program is described as either involving taking a pill or playing a video game on a daily basis for four weeks. In addition, participants were asked to imagine either their own child bullying another student at school, or their own child being bullied by another student. This resulted in a 2 × 2 between-subjects design. In an escalating series of morally challenging questions, we asked participants to rate their overall support for the program; whether they would support requiring participation; whether they would support requiring participation of children who are at higher risk to become bullies in the future; whether they would support requiring participation of all children or even the entire population; and whether they would be willing to participate in the program themselves. We found that people were significantly more troubled by pharmacological as opposed to non-pharmacological moral enhancement interventions. The results indicate that members of the public for the greater part oppose pharmacological moral bioenhancement, yet are open to non-biomedical means to attain moral enhancement. [248 words]

    The ethical desirability of moral bioenhancement: A review of reasons

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    Background: The debate on the ethical aspects of moral bioenhancement focuses on the desirability of using biomedical as opposed to traditional means to achieve moral betterment. The aim of this paper is to systematically review the ethical reasons presented in the literature for and against moral bioenhancement. Discussion: A review was performed and resulted in the inclusion of 85 articles. We classified the arguments used in those articles in the following six clusters: (1) why we (don't) need moral bioenhancement, (2) it will (not) be possible to reach consensus on what moral bioenhancement should involve, (3) the feasibility of moral bioenhancement and the status of current scientific research, (4) means and processes of arriving at moral improvement matter ethically, (5) arguments related to the freedom, identity and autonomy of the individual, and (6) arguments related to social/group effects and dynamics. We discuss each argument separately, and assess the debate as a whole. First, there is little discussion on what distinguishes moral bioenhancement from treatment of pathological deficiencies in morality. Furthermore, remarkably little attention has been paid so far to the safety, risks and side-effects of moral enhancement, including the risk of identity changes. Finally, many authors overestimate the scientific as well as the practical feasibility of the interventions they discuss, rendering the debate too speculative. Summary: Based on our discussion of the arguments used in the debate on moral enhancement, and our assessment of this debate, we advocate a shift in focus. Instead of speculating about non-realistic hypothetical scenarios such as the genetic engineering of morality, or morally enhancing 'the whole of humanity', we call for a more focused debate on realistic options of biomedical treatment of moral pathologies and the concrete moral questions these treatments raise

    The DSM-5 criteria, level of arousal and delirium diagnosis: Inclusiveness is safer

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    © 2014 European Delirium Association et al.; licensee BioMed Central Ltd. Background: Delirium is a common and serious problem among acutely unwell persons. Alhough linked to higher rates of mortality, institutionalisation and dementia, it remains underdiagnosed. Careful consideration of its phenomenology is warranted to improve detection and therefore mitigate some of its clinical impact. The publication of the fifth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-5) provides an opportunity to examine the constructs underlying delirium as a clinical entity.Discussion: Altered consciousness has been regarded as a core feature of delirium; the fact that consciousness itself should be physiologically disrupted due to acute illness attests to its clinical urgency. DSM-5 now operationalises 'consciousness' as 'changes in attention'. It should be recognised that attention relates to content of consciousness, but arousal corresponds to level of consciousness. Reduced arousal is also associated with adverse outcomes. Attention and arousal are hierarchically related; level of arousal must be sufficient before attention can be reasonably tested.Summary: Our conceptualisation of delirium must extend beyond what can be assessed through cognitive testing (attention) and accept that altered arousal is fundamental. Understanding the DSM-5 criteria explicitly in this way offers the most inclusive and clinically safe interpretation
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