The Role of NLRP3 in Regulation of Antimicrobial Peptides and Estrogen Signaling in UPEC-Infected Bladder Epithelial Cells.

The NLRP3 inflammasome, estrogen and antimicrobial peptides have all been found to have a vital role in the protection of the bladder urothelium. However, the interdependence between these protective factors during a bladder infection is currently unknown. Our aim was to investigate the role of NLRP3 in the regulation of antimicrobial peptides and estrogen signaling in bladder epithelial cells during a UPEC infection. Human bladder epithelial cells and CRISPR/Cas9-generated NLRP3-deficient cells were stimulated with the UPEC strain CFT073 and estradiol. The gene and protein expression were evaluated with microarray, qRT-PCR, western blot and ELISA. Microarray results showed that the expression of most antimicrobial peptides was reduced in CFT073-infected NLRP3-deficient cells compared to Cas9 control cells. Conditioned medium from NLRP3-deficient cells also lost the ability to suppress CFT073 growth. Moreover, NLRP3-deficient cells had lower basal release of Beta-defensin-1, Beta-defensin-2 and RNase7. The ability of estradiol to induce an increased expression of antimicrobial peptides was also abrogated in NLRP3-deficient cells. The decreased antimicrobial peptide expression might be linked to the observed reduced expression and activity of estradiol receptor beta in NLRP3-deficient cells. This study suggests that NLRP3 may regulate the release and expression of antimicrobial peptides and affect estrogen signaling in bladder epithelial cells.

The role of caspase-1, caspase-4 and NLRP3 in regulating the host cell response evoked by uropathogenic Escherichia coli.

The inflammasome-associated proteins caspase-1, caspase-4 and NLRP3 have been emphasised to be essential in the host cell response during urinary tract infection (UTI) by regulating IL-1ß release. Our aim was to investigate how the inflammasome-associated proteins regulate the cell response of bladder epithelial cells during infection with uropathogenic Escherichia coli (UPEC). Human bladder epithelial cells (5637) and CRISPR/Cas9 generated caspase-1, caspase-4 and NLRP3 knockdown cells were stimulated with the UPEC strain CFT073. Using Olink proteomics and real time RT-PCR, we showed that caspase-1, caspase-4 and NLRP3 are vital for the expression of many inflammatory genes and proteins from bladder epithelial cells. When investigating the effect of inflammasome-associated proteins on neutrophils, we found that conditioned medium from UPEC-infected caspase-4 knockdown cells significantly increased phagocytosis of CFT073 and significantly decreased ROS production from neutrophils. In contrast, conditioned medium from UPEC-infected NLRP3 knockdown cells significantly decreased the phagocytosis of CFT073 and significantly increased the ROS production from neutrophils. In conclusion, we showed that the inflammasome-associated proteins contribute to the host cell response during UPEC infection.

Trends in Swedish physicians' attitudes towards physician-assisted suicide: a cross-sectional study.

AIMS: To examine attitudes towards physician-assisted suicide (PAS) among physicians in Sweden and compare these with the results from a similar cross-sectional study performed in 2007. PARTICIPANTS: A random selection of 250 physicians from each of six specialties (general practice, geriatrics, internal medicine, oncology, surgery and psychiatry) and all 127 palliative care physicians in Sweden were invited to participate in this study. SETTING: A postal questionnaire commissioned by the Swedish Medical Society in collaboration with Karolinska Institute in Stockholm. RESULTS: The total response rate was 59.2%. Slightly fewer than half [47.1% (95% CI 43.7-50.5)] of the respondents from the six specialties accepted PAS, which is significantly more than accepted PAS in the 2007 study [34.9% (95% CI 31.5-38.3)]. Thirty-three percent of respondents were prepared to prescribe the needed drugs. When asked what would happen to the respondent's own trust in healthcare, a majority [67.1% (95% CI 63.9-70.3)] stated that legalizing PAS would either not influence their own trust in healthcare, or that their trust would increase. This number is an increase compared to the 2007 survey, when just over half [51.9% (95% CI 48.0-55.2)] indicated that their own trust would either not be influenced, or would increase. CONCLUSIONS: The study reveals a shift towards a more accepting attitude concerning PAS among physicians in Sweden. Only a minority of the respondents stated that they were against PAS, and a considerable proportion reported being prepared to prescribe the needed drugs for patient self-administration if PAS were legalized.

The Incidence of Intestinal Gastric Cancer among Resettlers in Germany-Do Resettlers Remain at an Elevated Risk in Comparison to the General Population?

OBJECTIVE: Previous studies have shown that the incidence of gastric cancer (GC), and particularly intestinal GC, is higher among resettlers from the former Soviet Union (FSU) than in the general German population. Our aim was to investigate if the higher risk remains over time. METHODS: GC cases between 1994 and 2013, in a cohort of 32,972 resettlers, were identified by the respective federal cancer registry. Age-standardized rates (ASRs) and standardized incidence ratios (SIRs) were analyzed in comparison to the general population for GC subtypes according to the Laurén classification. Additionally, the cohort was pooled with data from a second resettler cohort from Saarland to investigate time trends using negative binomial regression. RESULTS: The incidence of intestinal GC was elevated among resettlers in comparison to the general population (SIR (men) 1.64, 95% CI: 1.09-2.37; SIR (women) 1.91, 95% CI: 1.15-2.98). The analysis with the pooled data confirmed an elevated SIR, which was stable over time. CONCLUSION: Resettlers' higher risk of developing intestinal GC does not attenuate towards the incidence in the general German population. Dietary and lifestyle patterns might amplify the risk of GC, and we believe that further investigation of risk behaviors is needed to better understand the development of disease pattern among migrants.

A palliative care approach in psychiatry: clinical implications.

BACKGROUND: Traditionally, palliative care has focused on patients suffering from life-threatening somatic diseases such as cancer or progressive neurological disorders. In contrast, despite the often chronic, severely disabling, and potentially life-threatening nature of psychiatric disorders, there are neither palliative care units nor clinical guidelines on palliative measures for patients in psychiatry. MAIN TEXT: This paper contributes to the growing literature on a palliative approach in psychiatry and is based on the assumption that a change of perspective from a curative to a palliative approach could help promote patient-centeredness and increase quality of life for severely ill patients in psychiatry as well as in somatic medicine. To exemplify this, we offer three different clinical scenarios: severe and enduring anorexia nervosa, treatment-refractory schizophrenia, and chronic suicidality and persistent self-injury in borderline personality disorder. CONCLUSION: We emphasize that many typical interventions for treatment-refractory psychiatric disorders may indeed be of a palliative nature. Furthermore, introducing traditional features of palliative care, e.g. so-called goals of care conversations, could aid even further in ensuring that caregivers, patients, and families agree on which treatment goals are to be prioritized in order to optimize quality of life in spite of severe, persistent mental disorder.

IL-1RA is part of the inflammasome-regulated immune response in bladder epithelial cells and influences colonization of uropathogenic E. coli.

The NLRP3 inflammasome, IL-1ß release and pyroptosis (cell lysis) have recently been proposed to be essential for the progression of urinary tract infection (UTI) and elimination of intracellular bacterial niches. However, the effects of IL-1R antagonist (IL-1RA) on immune responses during UTI, except for its ability to disrupt IL-1ß signalling, are not well understood. The aim of this study was to investigate the role of IL-1RA in UPEC colonization of bladder epithelial cells and the subsequent host inflammatory response. Human bladder epithelial cells (5637) and CRISPR/Cas9 generated NLRP3 and caspase-1 knockdown cells and IL-1RA knockout cells were stimulated with the UPEC isolate CFT073. The results showed that the UPEC virulence factor α-hemolysin is essential for IL-1RA release, and that the inflammasome-associated proteins caspase-1 and NLRP3 affect the release of IL-1RA. IL-1RA deficient cells showed a reduced adherence and invasion by CFT073 compared to wild-type cells, suggesting that IL-1RA may oppose mechanisms that protects against bacterial colonization. A targeted protein analysis of inflammation-related proteins showed that the basal expression of 23 proteins and the UPEC-induced expression of 10 proteins were significantly altered in IL-1RA deficient bladder epithelial cells compared to Cas9 control cells. This suggests that IL-1RA has a broad effect on the inflammatory response in bladder epithelial cells.

Towards a palliative care approach in psychiatry: do we need a new definition?

Psychiatry today is mainly practised within a curative framework. However, many mental disorders are persistent and negatively affect quality of life as well as life expectancy. This tension between treatment goals and the actual illness trajectory has evoked a growing academic interest in 'palliative psychiatry', namely the application of a palliative care approach in patients with severe persistent mental illness. Recently, Trachsel et al presented a working definition of palliative psychiatry. This first official attempt to capture the concept is based on WHO's widely accepted definition of palliative care but modified and limited to include only severe persistent psychiatric illness. While this is a welcome step in the discussion on palliative care approaches in psychiatry, it also opens up for new questions. One of the most evident is whether psychiatry actually needs its own definition of palliative care or, put differently, whether there is something about mental disorders that differs so radically from other medical conditions that it calls for a separate definition. We acknowledge the need to discuss the goals of psychiatric care in patients with severe persistent psychiatric illness. However, we question whether a separate definition of palliative care exclusive to psychiatry is the right way to go. In this paper, we discuss why.

End-of-life decisions and the reinvented Rule of Double Effect: a critical analysis.

The Rule of Double Effect (RDE) holds that it may be permissible to harm an individual while acting for the sake of a proportionate good, given that the harm is not an intended means to the good but merely a foreseen side-effect. Although frequently used in medical ethical reasoning, the rule has been repeatedly questioned in the past few decades. However, Daniel Sulmasy, a proponent who has done a lot of work lately defending the RDE, has recently presented a reformulated and more detailed version of the rule. Thanks to its greater precision, this reinvented RDE avoids several problems thought to plague the traditional RDE. Although an improvement compared with the traditional version, we argue that Sulmasy's reinvented RDE will not stand closer scrutiny. Not only has the range of proper applicability narrowed significantly, but, more importantly, Sulmasy fails to establish that there is a morally relevant distinction between intended and foreseen effects. In particular, he fails to establish that there is any distinction that can account for the alleged moral difference between sedation therapy and euthanasia.

Moral differences in deep continuous palliative sedation and euthanasia.

In palliative care there is much debate about which end of life treatment strategies are legitimate and which are not. Some writers argue that there is an important moral dividing-line between palliative sedation and euthanasia, making the first acceptable and the latter not. We have questioned this. In a recent article, Lars Johan Materstvedt has argued that we are wrong on two accounts: first, that we fail to account properly for the moral difference between continuous deep palliative sedation at the end of life and euthanasia, and, second, that we fail to account properly for the difference between permanent loss of consciousness and death. Regarding the first objection, we argue that Materstvedt misses the point: we agree that there is a difference in terms of intentions between continuous deep palliative sedation and euthanasia, but we question whether this conceptual difference makes up for a moral difference. Materstvedt fails to show that it does. Regarding the second objection, we argue that if nothing else is at stake than the value of the patient's life, permanent unconsciousness and death are morally indifferent.

Veterinary surgeons' attitudes towards physician-assisted suicide: an empirical study of Swedish experts on euthanasia.

AIM: To examine the hypothesis that knowledge about physician-assisted suicide (PAS) and euthanasia is associated with a more restrictive attitude towards PAS. DESIGN: A questionnaire about attitudes towards PAS, including prioritization of arguments pro and contra, was sent to Swedish veterinary surgeons. The results were compared with those from similar surveys of attitudes among the general public and physicians. PARTICIPANTS: All veterinary surgeons who were members of the Swedish Veterinary Association and had provided an email address (n=2421). MAIN OUTCOME MEASURES: Similarities or differences in response pattern between veterinary surgeons, physicians and the general public. RESULTS: The response pattern among veterinary surgeons and the general public was almost similar in all relevant aspects. Of the veterinarians 75% (95% CI 72% to 78%) were in favour of PAS, compared with 73% (95% CI 69% to 77%) among the general public. Only 10% (95% CI 5% to 15%) of the veterinary surgeons were against PAS, compared with 12% (95% CI 5% to 19%) among the general public. Finally, 15% (95% CI 10% to 21%) of veterinarians were undecided, compared with 15% (95% CI 8% to 22%) among the general public. Physicians had a more restrictive attitude to PAS than the general public. CONCLUSIONS: Since veterinary surgeons have frequent practical experience of euthanasia in animals, they do have knowledge about what euthanasia really is. Veterinary surgeons and the general public had an almost similar response pattern. Accordingly it seems difficult to maintain that knowledge about euthanasia is unambiguously associated with a restrictive attitude towards PAS.

Physician-assisted suicide: a survey of attitudes among Swedish physicians.

AIMS: To investigate the attitudes of Swedish physicians towards physician-assisted suicide. DESIGN: A postal questionnaire on the respondent's opinion of physician-assisted suicide was sent to a randomly selected sample of physicians in Sweden. The respondents were given the opportunity of furnishing arguments of their own and of prioritizing arguments. They were also asked about possible influence on their own and patients' trust in the healthcare system if physician-assisted suicide was to be legally accepted. PARTICIPANTS: 1,200 physicians from six specialties, approximately 200 individuals each in: general practice, geriatrics, internal medicine, oncology, psychiatry and surgery. SETTING: The study was commissioned by the Swedish Medical Society and its logo was printed on questionnaires and envelopes. RESULTS: The total response rate was 74%, ranging between 63%-80% among the specialties. On average 34% were pro physician-assisted suicide, 39% against it and 25% were doubtful; 2% per cent did not respond to the question at all. Psychiatrists were significantly more accepting than oncologists, who were the most restrictive specialty. Older physicians (>50 years) provided a significantly more accepting attitude than younger ones (