Systemic Administration of Tolerogenic Dendritic Cells Ameliorates Murine Inflammatory Arthritis

The expression of various cell surface molecules and the production of certain cytokines are important mechanisms by which dendritic cells (DC) are able to bias immune responses. This paper describes the effects of the inflammatory cytokine tumor necrosis factor (TNF)-α on DC phenotype and function. TNF-α treatment resulted in upregulation of MHC class II and CD86 in the absence of increased cell surface CD40 and CD80 or the production of IL-12. Additionally TNF-α treated cells were able to bias T cell responses towards an anti-inflammatory profile. On a note of caution this tolerogenic phenotype of the DC was not stable upon subsequent TLR-4 ligation as a 4 hour pulse of the TNF-α treated DC with lipopolysaccharide (LPS) resulted in the restoration of IL-12 production and an enhancement of their T cell stimulatory capacity which resulted in an increased IFN-γ production. However, TNF-α treated DC, when administered in vivo, were shown to ameliorate disease in collagen induced arthritis, an experimental model of inflammatory joint disease. Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis. Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints. In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state

Natural Killer Cells in Kidney Health and Disease

Natural killer (NK) cells are a specialized population of innate lymphocytes that have a major effector function in local immune responses. While their immunological functions in many inflammatory diseases are well established, comparatively little is still known about their roles in kidney homeostasis and disease. Our understanding of kidney NK cells is rapidly evolving, with murine studies highlighting the functional significance of NK cells in acute and chronic forms of renal disease. Recent progress has been made in translating these murine findings to human kidneys, with indications of NK cell subset-specific roles in disease progression in both native and allograft kidneys. Clearly, a better understanding of the molecular mechanisms driving NK cell activation and importantly, their downstream interactions with intrinsic renal cells and infiltrating immune cells is necessary for the development of targeted therapeutics to halt disease progression. In this review, we discuss the properties and potential functions of kidney NK cells

Molecular Structure Studies of (1S,2S)-2-benzyl-2,3-dihydro-2-(1Hinden- 2-yl)-1H-inden-1-ol

The single enantiomer (1S,2S)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol (2), has recently been synthesized and isolated from its corresponding diastereoisomer (1). The molecular and crystal structures of this novel compound have been fully analyzed. The relative and absolute configurations have been determined by using a combination of analytical tools including X-ray crystallography, X-ray Powder Diffraction (XRPD) analysis and Nuclear Magnetic Resonance (NMR) spectroscopy

Calcific Uremic Arteriolopathy in Peritoneal Dialysis Populations

Calciphylaxis or calcific uremic arteriolopathy is an infrequent complication of end stage kidney disease. It is characterized by arteriolar medial calcification, thrombotic cutaneous ischemia, tissue necrosis often leading to ulceration, secondary infection and increased mortality rates. Current, multimodality treatment involves local wound care, well-controlled calcium, phosphate and parathyroid hormone levels and combination therapy with sodium thiosulfate and hyperbaric oxygen therapy. This combination therapy may be changing the historically poor prognosis of calcific uremic arteriolopathy reported in the literature. Peritoneal dialysis is considered a risk factor based on limited publications, however this remains to be proven. Clinical presentation, diagnosis, pathogenesis and treatment of calcific uremic arteriolopathy in these patients are no different from other patients manifesting with this condition

Randomised Controlled Trial to determine the appropriate time to initiate peritoneal dialysis after insertion of catheter to minimise complications (Timely PD study)

Background. The most appropriate time to initiate dialysis after surgical insertion of Tenckhoff catheters is not clear in the literature. There is the possibility of peritoneal dialysis (PD) complications such as leakage and infection if dialysis is started too soon after insertion. However, much morbidity and expense could be saved by reducing dependency on haemodialysis (HD) by earlier initiation of PD post catheter insertion. Previous studies are observational and mostly compare immediate with delayed use. The primary objective is to determine the safest and shortest time interval between surgical placement of a Tenckhoff catheter and starting PD. Methods/Design. This is a randomised controlled trial of patients who will start PD after insertion of Tenckhoff catheter at Royal Brisbane and Women's Hospital (RBWH) or Rockhampton Base Hospital (RBH) who meet the inclusion criteria. Patients will be stratified by site and diabetic status. The patients will be randomised to one of three treatment groups. Group 1 will start PD one week after Tenckhoff catheter insertion, group 2 at two weeks and group 3 at four weeks. Nurses and physicians will be blinded to the randomised allocation. The primary end point is the complication rate (leaks and infection) after initiation of PD. Discussion. The study will determine the most appropriate time to initiate PD after placement of a Tenckhoff catheter

Towards a new paradigm of care: the International Declaration on Youth Mental Health.

A recent and growing body of evidence on young people\u27s mental health has pointed to the need for an international response to the increasing and concerning rates of mental ill-health among young people.[1, 2] The periods of adolescence and emerging adulthood[3] are considered the peak periods for the onset of mental ill-health[4] with 75% of all adult diagnoses of mental ill-health having had an onset before the age of 25 years.[5] In an era when the physical health of young people has never been better,[6] their psychological and mental health has never been worse.[7] This leaves young people vulnerable to developing potentially intractable and enduring mental health difficulties with the inevitable personal, familial, social and vocational consequences that accompany the experience of mental ill-health.[4, 8] In spite of growing concerns about young people\u27s mental health, service provision for young people remains largely inadequate and unsuited to their needs. A number of systemic factors can be implicated in insufficient and unsuitable mental health service provision for young people. Internationally, there has been an endemic failure to invest in mental health across the lifespan with an average global spend on mental health of less than $US3 per capita per year.[9] This global underinvestment brings with it particular challenges in relation to the level of priority afforded to youth mental health and the concurrent commitment needed to respond to the scale of young people\u27s mental health needs. Even in developed countries where mental health services exist, there are widespread problems with services targeting young people. Primary care and other front line community agencies can struggle to respond to high levels of need, often with little support from specialist mental health services. Specialist mental health services have traditionally followed a paediatric-adult split, with child and adolescent services offering intervention until the largely arbitrary ages of 16 or 18 years and adult services taking all young people 18 years and older.[1] In many instances, there have been gaps in service provision between the ages of 16 and 18 years.[10] This has resulted in many young people being unable to access specialist mental health support during these critical years along with high rates of attrition and dissatisfaction by young people during this transitional period.[11, 12] With a recognition that, in many sociocultural contexts, the transition from adolescence to adulthood is a variable one that spans a period from the mid-teens to the mid- to late-20s,[13] both young people and youth mental health advocates have called for a reorganization of mental health services to mirror this extended developmental period for young people.[2] Not surprisingly, there has been a trend of poor help seeking and engagement by young people in mental health services.[14, 15] A key challenge remains in supporting young people to reach out for help when they need it and early evidence suggests that factors such as ease of access, the physical environment, location, atmosphere, branding and peer influence can promote help seeking among young people.[12] It must be noted, however, that even when services are youth friendly and appropriate to their needs, individual and psychological factors strongly influence help-seeking behaviour among young people experiencing emotional or psychological distress.[16, 17] From both an economic[18] and a human impact perspective, there is a strong rationale to invest in efforts to tackle the reality of mental ill-health among the youth population.[2] Efforts to establish a new youth mental health paradigm have already begun and are gaining momentum internationally, reflected most recently in the establishment of a new International Association for Youth Mental Health (http://www.iaymh.org). The first International Youth Mental Health Conference was held in Melbourne, Australia, in 2010 and the second is being held in 2013 in Brighton, the UK (http://www.iaymh2013.com). Those involved in the youth mental health movement recognize that positively impacting on young people\u27s mental health trajectories requires transformative change. Along with a need for early promotion, detection and intervention, stemming the tide of mental ill-health among young people requires a fundamental change in how we think about young people and their mental health. It demands that we challenge traditional approaches to service development and delivery and replace them with approaches that are inclusive and empowering for young people and their families. Young people and their families need to be involved in designing and implementing more creative, responsive, accessible and youth-friendly mental health services that have the capacity to meet their needs

Effectiveness of appropriately trained nurses in preoperative assessment: randomised controlled equivalence/non-inferiority trial

Objective To determine whether preoperative assessments carried out by appropriately trained nurses are inferior in quality to those carried out by preregistration house officers. Design Randomised controlled equivalence/non-inferiority trial. Setting Four NHS hospitals in three trusts. Three of the four were teaching hospitals. Participants All patients attending for assessment before general anaesthesia for general, vascular, urological, or breast surgery between April 1998 and March 1999. Intervention Assessment by one of three appropriately trained nurses or by one of several preregistration house officers. Main outcome measures History taken, physical examination, and investigations ordered. Measures evaluated by a specialist registrar in anaesthetics and placed in four categories: correct, overassessment, underassessment not affecting management, and underassessment possibly affecting management (primary outcome). Results 1907 patients were randomised, and 1874 completed the study; 926 were assessed by house officers and 948 by nurses. Overall 121/948 (13%) assessments carried out by nurses were judged to have possibly affected management compared with 138/926 (15%) of those performed by house officers. Nurses were judged to be non-inferior to house officers in assessment, although there was variation among them in terms of the quality of history taking. The house officers ordered considerably more unnecessary tests than the nurses (218/926 (24%) v 129/948 (14%). Conclusions There is no reason to inhibit the development of nurse led preoperative assessment provided that the nurses involved receive adequate training. However, house officers will continue to require experience in preoperative assessment

Cellular milieu in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC

Raman Spectroscopic Analysis of Human Skin Tissue Sections Ex-vivo: Evaluation of the Effects of Tissue Processing and Dewaxing

Raman spectroscopy coupled with K-means clustering analysis (KMCA) is employed to elucidate the biochemical structure of human skin tissue sections, and the effects of tissue processing. Both hand and thigh sections of human cadavers were analysed in their unprocessed and formalin fixed paraffin processed (FFPP) and subsequently dewaxed forms. In unprocessed sections, KMCA reveals clear differentiation of the stratum corneum, intermediate underlying epithelium and dermal layers for sections from both anatomical sites. The stratum corneum is seen to be relatively rich in lipidic content; the spectrum of the subjacent layers is strongly influenced by the presence of melanin, while that of the dermis is dominated by the characteristics of collagen. For a given anatomical site, little difference in layer structure and biochemistry is observed between samples from different cadavers. However, the hand and thigh sections are consistently differentiated for all cadavers, largely based on lipidic profiles. In dewaxed FFPP samples, while the stratum corneum, intermediate and dermal layers are clearly differentiated by KMCA of Raman maps of tissue sections, the lipidic contributions to the spectra are significantly reduced, with the result that respective skin layers from different anatomical sites become indistinguishable. While efficient at removing the fixing wax, the tissue processing also efficiently removes the structurally similar lipidic components of the skin layers. In studies of dermatological processes in which lipids play an important role, such as wound healing, dewaxed samples are therefore not appropriate. Removal of the lipids does however accentuate the spectral features of the cellular and protein components, which may be more appropriate for retrospective analysis of disease progression and biochemical analysis using tissue banks

Prevalence of Parvovirus B19 Viremia Among German Blood Donations and the Relationship to ABO and Rhesus Blood Group Antigens

Background Asymptomatic blood donors can transmit human parvovirus B19 (B19V). Methods We assessed the B19V prevalence among a large cohort of blood donations collected in Germany during 2015–2018. Results In total, 167 123 donations were screened for B19V deoxyribonucleic acid with 22 cases of viremia identified (0.013% positive). Infections peaked at a 4-year interval and the highest number of cases occurred in the summer months. All 22 infections were found in rhesus D-antigen-positive donations, suggesting a protective factor in donors who lack this antigen. Conclusions These findings contribute to our understanding of risk factors for B19V infection among central European blood and plasma donors