Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury.

BACKGROUND: Administration of granulocyte-macrophage colony stimulating factor (GM-CSF) relieves symptoms in Crohn's disease (CD). It has been reported that reduced GM-CSF bioactivity is associated with more aggressive ileal behaviour and that GM-CSF-null mice exhibit ileal barrier dysfunction and develop a transmural ileitis following exposure to non-steroidal anti-inflammatory drugs (NSAIDs). STAT5 signalling is central to GM-CSF action. It was therefore hypothesised that GM-CSF signalling in non-haematopoietic cells is required for ileal homeostasis. METHODS: Bone marrow (BM) chimeras were generated by reconstituting irradiated GM-CSF receptor (gm-csfr) beta chain or GM-CSF (gm-csf) deficient mice with wild type BM (WTBM-->GMRKO and WTBM-->GMKO). Intestinal barrier function and the response to NSAID-induced ileal injury were examined. Expression of gm-csf, gm-csfr or stat5 in Caco-2 and HT-29 intestinal epithelial cell (IEC) lines was knocked down and the effect of GM-CSF signalling on IEC survival and proliferation was determined. RESULTS: Elevated levels of GM-CSF autoantibodies in ileal CD were found to be associated with dysregulation of IEC survival and proliferation. GM-CSF receptor-deficient mice and WTBM-->GMRKO chimeras exhibited ileal hyperpermeability. NSAID exposure induced a transmural ileitis in GM-CSF receptor-deficient mice and WTBM-->GMRKO chimeras. Transplantation of wild type BM into GM-CSF-deficient mice prevented NSAID ileal injury and restored ileal barrier function. Ileal crypt IEC proliferation was reduced in WTBM-->GMRKO chimeras, while STAT5 activation in ileal IEC following NSAID exposure was abrogated in WTBM-->GMRKO chimeras. Following knock down of gm-csf, gm-csfr alpha or beta chain or stat5a/b expression in Caco-2 cells, basal proliferation was suppressed. GM-CSF normalised proliferation of Caco-2 cells exposed to NSAID, which was blocked by stat5a/b RNA interference. CONCLUSIONS: Loss of GM-CSF signalling in non-haematopoietic cells increases NSAID ileal injury; furthermore, GM-CSF signalling in non-haematopoietic cells regulates ileal epithelial homeostasis via the STAT5 pathway. The therapeutic use of GM-CSF may therefore be beneficial in chronic ileitis associated with CD.

A Survey of Hospice and Palliative Care Clinicians' Experiences and Attitudes Regarding the Use of Palliative Sedation.

BACKGROUND: A variety of terms and attitudes surround palliative sedation (PS) with little research devoted to hospice and palliative care (HPC) clinicians' perceptions and experiences with PS. These factors may contribute to the wide variability in the reported prevalence of PS. OBJECTIVE: This study was designed to better identify hospice and palliative care (HPC) clinician attitudes toward, and clinical experiences with palliative sedation (PS). METHODS: A 32-question survey was distributed to members of the American Academy of Hospice and Palliative Medicine (n = 4678). The questions explored the language clinicians use for PS, and their experiences with PS. RESULTS: Nine hundred thirty-six (20% response rate) responded to the survey. About 83.21% preferred the terminology of PS compared with other terms. A majority felt that PS is a bioethically appropriate treatment for refractory physical and nonphysical symptoms in dying patients. Most felt PS was not an appropriate term in clinical scenarios when sedation occurred as an unintended side effect from standard treatments. Hospice clinicians use PS more consistently and with less distress than nonhospice clinician respondents. Benzodiazepines (63.1%) and barbiturates (18.9%) are most commonly prescribed for PS. CONCLUSION: PS is the preferred term among HPC clinicians for the proportionate use of pharmacotherapies to intentionally lower awareness for refractory symptoms in dying patients. PS is a bioethically appropriate treatment for refractory symptoms in dying patients. However, there is a lack of clear agreement about what is included in PS and how the practice of PS should be best delivered in different clinical scenarios. Future efforts to investigate PS should focus on describing the clinical scenarios in which PS is utilized and on the level of intended sedation necessary, in an effort to better unify the practice of PS.

The Interplay of Factitious Disorder and Palliative Care Encounters: A Case Series.

BACKGROUND: Individuals with factitious disorders often suffer emotional pain, which motivates them to assume a "sick role" rather than experience the intensity of emotional distress. Such individuals may experience iatrogenic harm as a consequence of their psychological disorder. Their clinicians may develop strong negative emotions such as disgust and the health care system can accrue increased medical costs from diagnostic dilemmas. If the disorder remains unrecognized, the resulting tension can cause interdisciplinary team (IDT) conflicts and impact the effectiveness of care. METHODS: In this article, we describe three cases of factitious behaviors, as either a comorbid illness or an underlying condition, that potentiate untoward health effects among patients seen by a palliative care team. We use these examples to illustrate common features of factious disorders, identify clinical pitfalls when caring for such patients, and offer care strategies for palliative care providers who may encounter such patients with increasing prevalence considering the larger national push to involve palliative care teams earlier in disease trajectories.