The care of dying people in 16th- and 17th-century England

Between the years 1500 and 1700, mortality was higher and exposure to death is greater than in the modern day. Through analysis of primary texts from the chosen period, we explored the principles behind the care of the dying in the context of medicine, spirituality, and society. Results showed that a "holy death" was a cultural norm and medicine was subsidiary: hope was for the salvation of the soul, not the body. This was part of an approach that focused on symptom relief, irrespective of disease classification, demonstrating an early holistic approach to death and dying

Combining creative writing and narrative analysis to deliver new insights into the impact of pulmonary hypertension

Introduction Pulmonary hypertension is life-limiting. Delays in diagnosis are common, and even after treatment has been initiated, pulmonary hypertension has marked effects on many aspects of social and physical function. We believed that a new approach to examining disease impact could be achieved through a combination of narrative research and creative writing. Methods Detailed unstructured narrative interviews with people with pulmonary hypertension were analysed thematically. Individual moments were also summarised and studied using creative writing, in which the interviewer created microstories from narrative and interview data. Stories were shared with their subjects, and with other patients, clinicians, researchers and the wider public. The study was carried out in hospital and in patients’ homes. Results Narrative analysis generated a rich data set which highlighted profound effects of pulmonary hypertension on identity, and demonstrated how the disease results in very marked personal change with ongoing and unpredictable requirement for adaptation. The novel methodology of microstory development proved to be an effective tool to summarise, communicate, and explore the consequences of pulmonary hypertension and the clinical challenges of caring for patients with this illness. Conclusions A holistic approach to treatment of chronic respiratory diseases such as pulmonary hypertension requires and benefits from explicit exploration of the full impacts of the illness. Narrative analysis and the novel approach of targeted microstory development can form a valuable component of the repertoire of approaches to effectively comprehend chronic disease and can also facilitate patient-focused discussion and interventions

The utilization of cultural movements to overcome stigma in narrative of postnatal depression

Background: Despite affecting 15% of new mothers, experience of postnatal depression has often been hidden by stigma, cultural beliefs, and lack of medical understanding. We examined the barriers to women sharing their experience and gaining help, using their own words to illuminate the experiences of stigma and injustice. This study examines the narratives of women across the twentieth century, explores cultural movements that framed and contextualized their experiences, and marks how women became more empowered to speak of maternal distress. Methods: Narrative literature was identified via searches of literature catalogs. Narrative accounts provided a lens through which to analyze cultural understandings of postnatal depression according to historical method. Contemporary medical and sociological literature discussing postnatal depression was used to contextualize the social climate within which these narratives were written. This work combines historical analysis with philosophical framework to develop insight into patient experiences of mental ill-health and associated stigma. Results: This research identified three core cultural movements providing women with a framework in which to discuss their experiences of postnatal depression: the labor movement in the early twentieth century, the second-wave feminism movement in the mid-twentieth century (ca. 1960–1980), and the so-called “Prozac revolution” emerging at the end of the twentieth century. These movements provided distinct culturally acceptable etiologies around which women were able to frame their experience of postnatal depression. This provided women with space in which to share and process their experiences and aided them in overcoming contemporary stigma against mental illness by challenging disparaging stereotypes of the depressed mother. Conclusions: Despite the stigmatizing nature of mental illness, women have demonstrated resilience and ingenuity by utilizing acceptable cultural movements to reframe their experiences of postnatal depression, challenging traditional perceptions of motherhood and effectively earned recognition of their sufferings. During this period, concordance between patient perceptions of postnatal depression and clinical understandings of the condition has been variable. Highlighting the detriment to therapeutic relationship when discordance is present, the narrators have demonstrated the need to destigmatize illness and facilitate cooperation between physician and patient and remind clinicians of the importance of placing patient experience at the center of care

A method for transplantation of human HSCs into zebrafish, to replace humanised murine transplantation models

Haematopoietic stem cell (HSC) transplantation is a critical therapy for haematopoietic malignancies and immune disorders. Incomplete or delayed engraftment of HSCs in the host results in increased risk of infection and morbidity. The mechanisms of HSC engraftment are poorly understood and understanding these processes will increase transplantation success on many levels. Current animal models are immunocompromised 'humanised' mice transplanted with human HSCs. Harmful procedures include genetic manipulations and irradiation to ablate the mouse immune system, and opaque mouse tissues make visualisation of the early steps of HSC engraftment impossible. There is a need for new models to offer alternatives to humanised mice in the study of HSC transplantation. Here we described a detailed method for transplantation of human HSCs into zebrafish, before the onset of adaptive immunity. Human HSCs were purified from whole blood by enrichment of the CD34 cell population using a positive magnetic selection and further purified using an anti-CD34 antibody and cell sorting. Sorted CD34 cells were transplanted into the blood stream of 52 hour old zebrafish larvae. Human HSCs home into the zebrafish haematopoietic niche, where they engage with endothelial cells and undergo cell division. Our model offers the opportunities to image in vivo human HSC engraftment in a transparent organism, without the myeloablative strategies used in mice, and provides a unique system to understand the dynamic process of engraftment and replace current murine models. This technique can be applied to current engraftment protocols to validate the viability and efficiency of cryofrozen HSC grafts. This humanised zebrafish model will be instrumental to develop the 3Rs values in stem cell transplantation research and our detailed protocol will increase the chances of uptake of this zebrafish model by the mouse community

Pathophysiology and diagnosis of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease (PH-LHD) is the most common type of pulmonary hypertension, although an accurate prevalence is challenging. PH-LHD includes PH due to systolic or diastolic left ventricular dysfunction, mitral or aortic valve disease and congenital left heart disease. In recent years a new and distinct phenotype of “combined post-capillary and pre-capillary PH,” based on diastolic pulmonary gradient and pulmonary vascular resistance, has been recognized. The roles of right ventricular dysfunction and pulmonary vascular compliance in PH-LHD have also been elucidated recently and they appear to have significant clinical implications. Echocardiography continues to play a seminal role in diagnosis of PH-LHD and heart failure with preserved LV ejection fraction, as it can identify valve disease and help to distinguish PH-LHD from pre-capillary PH. Right, and occasionally left heart catheterization, remains the gold-standard for diagnosis and phenotyping of PH-LHD, although Cardiac Magnetic Resonance Imaging is emerging as a useful alternative tool in non-invasive diagnostic and prognostic assessment of PH-LHD. In this review, the latest evidence for more recent advances will be discussed, including the role of fluid challenge and exercise during cardiac catheterization to unravel occult post-capillary and the role of vasoreactivity testing. The use of many or all of these diagnostic techniques will undoubtedly provide key information about sub-groups of patients with PH-LHD that might benefit from medical therapy previously considered to be only suitable for pulmonary arterial hypertension

DUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus Through IL-1β Signalling

Rhinoviral infection is a common trigger of the excessive inflammation observed during exacerbations of asthma and chronic obstructive pulmonary disease. Rhinovirus (RV) recognition by pattern recognition receptors activates the MAPK pathways, common inducers of inflammatory gene production. A family of dual-specificity phosphatases (DUSPs) can regulate MAPK function, but their roles in rhinoviral infection are not known. We hypothesised that DUSPs would negatively regulate the inflammatory response to RV infection. Our results revealed that p38 and JNK MAPKs play key roles in the inflammatory response of epithelial cells to RV infection. Three DUSPs previously shown to have roles in innate immunity, 1, 4 and 10, were expressed in primary bronchial epithelial cells, one of which, DUSP10, was down regulated by RV infection. Small interfering-RNA knock down of DUSP10 identified a role for the protein in negatively regulating inflammatory cytokine production in response to IL-1β alone and in combination with RV, without any effect on RV replication. This study identifies DUSP10 as an important regulator of airway inflammation in respiratory viral infection

DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

Prostaglandin (PG) D2 is the ligand for the G‐protein coupled receptors DP1 (D‐type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro‐inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor‐mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which—as a consequence—sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti‐apoptotic gene BCL‐XL, but also induced pro‐inflammatory genes, such as VLA‐4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti‐apoptotic, early‐response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro‐inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti‐inflammatory therapy in eosinophilic diseases

A bittersweet response to infection in diabetes ; targeting neutrophils to modify inflammation and improve host immunity

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality