Dynamic expression of smRNA from fecal exosome in disease progression of an inflammatory bowel disorder mouse model

ABSTRACTInflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract affecting over 3 million adults in the United States. Despite being widespread, reliable early diagnostic tests are not available. We examined exosomal small RNA (smRNA), specifically targeting microRNA (miRNA) and piRNA from the stool samples of IBD model mice, interleukin 10 knockout mice (IL-10 KO), as a potential diagnostic marker. Stool samples were specifically chosen because they are readily available, and collection is noninvasive. At the end of the experimental period, the gastrointestinal (GI) tract was collected, and disease severity was scored. Histopathology showed a significant increase in inflammation and proliferation within the proximal and distal large intestines. smRNA profiles were examined upon conventional housing (start-point) which is a determinant factor of spontaneous IBD progression in the IL-10 KO mice, terminal illness (end-point), and 6 weeks before the end-point (mid-point), when the mice were still phenotypically healthy. We found 504 smRNA that were significantly differentially expressed between before symptom onset and terminal sedation. These changes were not detected in wild-type samples. Moreover, clustering analysis of expression changes over the disease progression identified a unique set of smRNAs that primarily target pro-inflammatory or anti-inflammatory genes. The expression of smRNAs that suppresses pro-inflammatory genes was higher at 6 weeks before terminal sedation, suggesting the downregulation of the pro-inflammatory genes advances the terminal illness of the IBD. In summary, our study proposes that fecal exosomal smRNA profiling offers a new opportunity to monitor the inflammatory status of the gut with a capability of detecting its pro-inflammatory (asymptomatic) status. Our next step is to understand the spatiotemporal interplay of these exosomes and the host cells in the gut as well as the complete biochemical makeup of fecal exosomes, such as mRNA, DNA, protein, and lipids. This will lead to an exciting development of reengineered exosomes that can be utilized to treat or even prevent the pro-inflammatory colonic lesion while the host is still clinically asymptomatic.

Patient’s Orders: Patient’s Rights and the Doctor’s Obligations under the Claeys–Leonetti Law of 2016 in France

France enacted the Claeys–Leonetti law in 2016, becoming one of the first countries to legalize terminal sedation as a medico-legal practice in the world. The focus of this short paper is to highlight the limitations imposed by Claeys–Leonetti on the doctor to fulfil his or her ethical duties under the Hippocratic oath to act ‘for the benefit of my patient’ but to act only according to the ‘wishes of the patient’, to eliminate all forms of pain and suffering. A legislative commentary will be provided for the first five pertinent articles followed by proposals for reform.

Euthanasia and palliative sedation in Belgium

The aim of this article is to use data from Belgium to analyse distinctions between palliative sedation and euthanasia. There is a need to reduce confusion and improve communication related to patient management at the end of life specifically regarding the rapidly expanding area of patient care that incorporates a spectrum of nuanced yet overlapping terms such as palliative care, sedation, palliative sedation, continued sedation, continued sedation until death, terminal sedation, voluntary euthanasia and involuntary euthanasia. Some physicians and nurses mistakenly think that relieving suffering at the end of life by heavily sedating patients is a form of euthanasia, when indeed it is merely responding to the ordinary and proportionate needs of the patient. Concerns are raised about abuse in the form of deliberate involuntary euthanasia, obfuscation and disregard for the processes sustaining the management of refractory suffering at the end of life. Some suggestions designed to improve patient management and prevent potential abuse are offered.

Terminal Sedation – Good Medicine? Good Ethics? Good Law?

<p><em><span style="font-family: Times New Roman; font-size: medium;">The use of sedation at the end of life is becoming increasingly common, yet its ethics and lawfulness have not been as widely discussed as might have been expected. In this article, the primary focus is on what is known as ‘terminal sedation’, with particular reference to the use of sedation without the provision of assisted nutrition and hydration (‘ANH’). It is argued that, where ANH is not contraindicated by patient wellbeing itself, close scrutiny of the practice is required. There are both ethical and legal reasons why a move towards appropriate regulation is appropriate. The urgency of doing this is evidenced by the variety in practices throughout the world, with some commentators suggesting that the decision whether or not to instigate terminal sedation may be influenced by more than clinical indications for its use (in which case, it may be perilously close to a form of euthanasia). Indeed, it may be argued that there is little that differentiates terminal sedation from a form of euthanasia. Moreover, the relatively common exclusion of existential suffering as an indication for terminal sedation is questioned. Were this also to be accepted as a valid indicator for terminal sedation (without the provision of ANH) it becomes even more urgent that an adequate regulatory framework is developed and that the ethics of the practice are appropriately explored and clarified.</span></em></p>