Human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis in hypoxic kidney injury.

Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). The mitochondrial-rich proximal tubular epithelial cells (PTEC) are uniquely sensitive to hypoxia and thus, are pivotal in propagating the sustained tubular loss of AKI-to-CKD transition. Here, we examined the role of PTEC-derived small extracellular vesicles (sEV) in propagating the 'wave of tubular death'. Ex vivo patient-derived PTEC were cultured under normoxia (21 % O2) and hypoxia (1 % O2) on Transwell inserts for isolation and analysis of sEV secreted from apical versus basolateral PTEC surfaces. Increased numbers of sEV were secreted from the apical surface of hypoxic PTEC compared with normoxic PTEC. No differences in basolateral sEV numbers were observed between culture conditions. Biological pathway analysis of hypoxic-apical sEV cargo identified distinct miRNAs linked with cellular injury pathways. In functional assays, hypoxic-apical sEV selectively induced ferroptotic cell death (↓glutathione peroxidase-4, ↑lipid peroxidation) in autologous PTEC compared with normoxic-apical sEV. The addition of ferroptosis inhibitors, ferrostatin-1 and baicalein, attenuated PTEC ferroptosis. RNAse A pretreatment of hypoxic-apical sEV also abrogated PTEC ferroptosis, demonstrating a role for sEV RNA in ferroptotic 'wave of death' signalling. In line with these in vitro findings, in situ immunolabelling of diagnostic kidney biopsies from AKI patients with clinical progression to CKD (AKI-to-CKD transition) showed evidence of ferroptosis propagation (increased numbers of ACSL4+ PTEC), while urine-derived sEV (usEV) from these 'AKI-to-CKD transition' patients triggered PTEC ferroptosis (↑lipid peroxidation) in functional studies. Our data establish PTEC-derived apical sEV and their intravesicular RNA as mediators of tubular lipid peroxidation and ferroptosis in hypoxic kidney injury. This concept of how tubular pathology is propagated from the initiating insult into a 'wave of death' provides novel therapeutic check-points for targeting AKI-to-CKD transition.

Bodies at play: the role of intercorporeality and bodily affordances in coordinating social play in chimpanzees in the wild.

The comparative approach is a crucial method to gain a better understanding of the behavior of living human and nonhuman animals to then draw informed inferences about the behavior of extinct ancestors. One focus has been on disentangling the puzzle of language evolution. Traditionally, studies have predominantly focused on intentionally produced signals in communicative interactions. However, in collaborative and highly dynamic interactions such as play, underlying intentionality is difficult to assess and often interactions are negotiated via body movements rather than signals. This "lack" of signals has led to this dynamic context being widely ignored in comparative studies. The aim of this paper is threefold: First, we will show how comparative research into communication can benefit from taking the intentionality-agnostic standpoint used in conversation analysis. Second, we will introduce the concepts of 'intercorporeality' and 'bodily affordance', and show how they can be applied to the analysis of communicative interactions of nonhuman animals. Third, we will use these concepts to investigate how chimpanzees (Pan troglodytes) initiate, end, and maintain 'contact social play'. Our results showed that bodily affordances are able to capture elements of interactions that more traditional approaches failed to describe. Participants made use of bodily affordances to achieve coordinated engagement in contact social play. Additionally, these interactions could display a sequential organization by which one 'move' by a chimpanzee was responded to with an aligning 'move', which allowed for the co-construction of the activity underway. Overall, the present approach innovates on three fronts: First, it allows for the analysis of interactions that are often ignored because they do not fulfil criteria of intentionality, and/or consist of purely body movements. Second, adopting concepts from research on human interaction enables a better comparison of communicative interactions in other animal species without a too narrow focus on intentional signaling only. Third, adopting a stance from interaction research that highlights how practical action can also be communicative, our results show that chimpanzees can communicate through their embodied actions as well as through signaling. With this first step, we hope to inspire new research into dynamic day-to-day interactions involving both "traditional" signals and embodied actions, which, in turn, can provide insights into evolutionary precursors of human language.

Hypoxic human proximal tubular epithelial cells undergo ferroptosis and elicit an NLRP3 inflammasome response in CD1c+ dendritic cells.

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O2) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c+ DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1ß and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1ß/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c+ DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD.

Molecular and functional profiling of apical versus basolateral small extracellular vesicles derived from primary human proximal tubular epithelial cells under inflammatory conditions.

Proximal tubular epithelial cells (PTEC) are central players in inflammatory kidney diseases. However, the complex signalling mechanism/s via which polarized PTEC mediate disease progression are poorly understood. Small extracellular vesicles (sEV), including exosomes, are recognized as fundamental components of cellular communication and signalling courtesy of their molecular cargo (lipids, microRNA, proteins). In this study, we examined the molecular content and function of sEV secreted from the apical versus basolateral surfaces of polarized human primary PTEC under inflammatory diseased conditions. PTEC were cultured under normal and inflammatory conditions on Transwell inserts to enable separate collection and isolation of apical/basolateral sEV. Significantly increased numbers of apical and basolateral sEV were secreted under inflammatory conditions compared with equivalent normal conditions. Multi-omics analysis revealed distinct molecular profiles (lipids, microRNA, proteins) between inflammatory and normal conditions for both apical and basolateral sEV. Biological pathway analyses of significantly differentially expressed molecules associated apical inflammatory sEV with processes of cell survival and immunological disease, while basolateral inflammatory sEV were linked to pathways of immune cell trafficking and cell-to-cell signalling. In line with this mechanistic concept, functional assays demonstrated significantly increased production of chemokines (monocyte chemoattractant protein-1, interleukin-8) and immuno-regulatory cytokine interleukin-10 by peripheral blood mononuclear cells activated with basolateral sEV derived from inflammatory PTEC. We propose that the distinct molecular composition of sEV released from the apical versus basolateral membranes of human inflammatory PTEC may reflect specialized functional roles, with basolateral-derived sEV pivotal in modulating tubulointerstitial inflammatory responses observed in many immune-mediated kidney diseases. These findings provide a rationale to further evaluate these sEV-mediated inflammatory pathways as targets for biomarker and therapeutic development.

Variation and Interactional Non-Standardization in Neuropsychological Tests: The Case of the Addenbrooke's Cognitive Examination.

The Addenbrooke's Cognitive Examination (ACE-111) is a neuropsychological test used in clinical practice to inform a dementia diagnosis. The ACE-111 relies on standardized administration so that patients' scores can be interpreted by comparison with normative scores. The test is delivered and responded to in interaction between clinicians and patients, which places talk-in-interaction at the heart of its administration. In this article, conversation analysis (CA) is used to investigate how the ACE-111 is delivered in clinical practice. Based on analysis of 40 video/audio-recorded memory clinic consultations in which the ACE-111 was used, we have found that administrative standardization is rarely achieved in practice. There was evidence of both (a) interactional variation in the way the clinicians introduce the test and (b) interactional non-standardization during its implementation. We show that variation and interactional non-standardization have implications for patients' understanding and how they might respond to particular questions.

Specialized Roles of Human Natural Killer Cell Subsets in Kidney Transplant Rejection.

Background: Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56bright cytokine-producing vs. CD56dim cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations. We report the outcomes of an innovative multi-color flow cytometric-based approach to unequivocally define and evaluate NK cell subsets in human kidney allograft rejection. Methods: We extracted renal lymphocytes from human kidney transplant biopsies. NK cell subsets were identified, enumerated, and phenotyped by multi-color flow cytometry. Dissociation supernatants were harvested and levels of soluble proteins were determined using a multiplex bead-based assay. Results were correlated with the histopathological patterns in biopsies-no rejection, borderline cellular rejection, T cell-mediated rejection (TCMR), and antibody-mediated rejection (AMR). Results: Absolute numbers of only CD56bright NK cells were significantly elevated in TCMR biopsies. In contrast, both CD56bright and CD56dim NK cell numbers were significantly increased in biopsies with histopathological evidence of AMR. Notably, expression of the activation marker CD69 was only significantly elevated on CD56dim NK cells in AMR biopsies compared with no rejection biopsies, indicative of a pathogenic phenotype for this cytotoxic NK cell subset. In line with this, we detected significantly elevated levels of cytotoxic effector molecules (perforin, granzyme A, and granulysin) in the dissociation supernatants of biopsies with a histopathological pattern of AMR. Conclusions: Our results indicate that human NK cell subsets are differentially recruited and activated during distinct types of rejection, suggestive of specialized functional roles.

Human Tissue-Resident Mucosal-Associated Invariant T (MAIT) Cells in Renal Fibrosis and CKD.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells represent a specialized lymphocyte population associated with chronic inflammatory disorders. Little is known, however, about MAIT cells in diseases of the kidney, including CKD. METHODS: To evaluate MAIT cells in human native kidneys with tubulointerstitial fibrosis, the hallmark of CKD, we used multicolor flow cytometry to identify, enumerate, and phenotype such cells from human kidney tissue biopsy samples, and immunofluorescence microscopy to localize these cells. We cocultured MAIT cells and human primary proximal tubular epithelial cells (PTECs) under hypoxic (1% oxygen) conditions to enable examination of mechanistic tubulointerstitial interactions. RESULTS: We identified MAIT cells (CD3+ TCR Vα7.2+ CD161hi) in healthy and diseased kidney tissues, detecting expression of tissue-resident markers (CD103/CD69) on MAIT cells in both states. Tissue samples from kidneys with tubulointerstitial fibrosis had significantly elevated numbers of MAIT cells compared with either nonfibrotic samples from diseased kidneys or tissue samples from healthy kidneys. Furthermore, CD69 expression levels, also an established marker of lymphocyte activation, were significantly increased on MAIT cells from fibrotic tissue samples. Immunofluorescent analyses of fibrotic kidney tissue identified MAIT cells accumulating adjacent to PTECs. Notably, MAIT cells activated in the presence of human PTECs under hypoxic conditions (modeling the fibrotic microenvironment) displayed significantly upregulated expression of CD69 and cytotoxic molecules perforin and granzyme B; we also observed a corresponding significant increase in PTEC necrosis in these cocultures. CONCLUSIONS: Our findings indicate that human tissue-resident MAIT cells in the kidney may contribute to the fibrotic process of CKD via complex interactions with PTECs.

Effector γδ T cells in human renal fibrosis and chronic kidney disease.

Background: γδ T cells are effector lymphocytes recognized as key players during chronic inflammatory processes. Mouse studies suggest a pathological role for γδ T cells in models of kidney disease. Here we evaluated γδ T cells in human native kidneys with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Methods: γδ T cells were extracted from human kidney tissue and enumerated and phenotyped by multicolour flow cytometry. Localization and cytokine production by γδ T cells was examined by immunofluorescent microscopy. Results: We detected significantly elevated numbers of γδ T cells in diseased biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue. At a subset level, only numbers of Vδ1+ γδ T cells were significantly elevated in fibrotic kidney tissue. Expression levels of cluster of differentiation 161 (CD161), a marker of human memory T cells with potential for innate-like function and interleukin (IL)-17A production, were significantly elevated on γδ T cells from fibrotic biopsies compared with nonfibrotic kidney tissue. Flow cytometric characterization of CD161+ γδ T cells in fibrotic biopsies revealed significantly elevated expression of natural killer (NK) cell-associated markers CD56, CD16 and CD336 (NKp44) compared with CD161- γδ T cells, indicative of a cytotoxic phenotype. Immunofluorescent analysis of fibrotic kidney tissue localized the accumulation of γδ T cells within the tubulointerstitium, with γδ T cells identified, for the first time, as a source of pro-inflammatory cytokine IL-17A. Conclusions: Collectively, our data suggest that human effector γδ T cells contribute to the fibrotic process and thus progression to chronic kidney disease.

Taking turns: bridging the gap between human and animal communication.

Language, humans' most distinctive trait, still remains a 'mystery' for evolutionary theory. It is underpinned by a universal infrastructure-cooperative turn-taking-which has been suggested as an ancient mechanism bridging the existing gap between the articulate human species and their inarticulate primate cousins. However, we know remarkably little about turn-taking systems of non-human animals, and methodological confounds have often prevented meaningful cross-species comparisons. Thus, the extent to which cooperative turn-taking is uniquely human or represents a homologous and/or analogous trait is currently unknown. The present paper draws attention to this promising research avenue by providing an overview of the state of the art of turn-taking in four animal taxa-birds, mammals, insects and anurans. It concludes with a new comparative framework to spur more research into this research domain and to test which elements of the human turn-taking system are shared across species and taxa.

Identification and Quantitation of Leukocyte Populations in Human Kidney Tissue by Multi-parameter Flow Cytometry.

Inflammatory immune cells play direct pathological roles in cases of acute kidney injury (AKI) and chronic kidney disease (CKD). However, the identification and characterization of distinct populations of leukocytes in human kidney biopsies have been confounded by the limitations of immunohistochemical (IHC)-based techniques used to detect them. This methodology is not amenable to the combinations of multiple markers necessary to unequivocally define discrete immune cell populations. We have developed a multi-parameter, flow cytometric-based approach that addresses the need for panels of cell-specific markers in the identification of immune cell populations, allowing both the accurate detection and quantitation of leukocyte subpopulations from a single, clinical kidney biopsy specimen. In this approach, fresh human kidney tissue is dissociated into a single cell suspension followed by antibody-labeling and flow cytometric-based acquisition and analysis. This novel technique provides a major step forward in identifying and enumerating immune cell subpopulations in human kidney disease and is a powerful platform to complement traditional histopathological examinations of clinical kidney biopsies.

Unique molecular profile of exosomes derived from primary human proximal tubular epithelial cells under diseased conditions.

Human proximal tubular epithelial cells (PTEC) of the kidney are known to respond to and mediate the disease process in a wide range of kidney diseases, yet their exosomal production and exosome molecular cargo remain a mystery. Here we investigate, for the first time, the production and molecular content of exosomes derived from primary human PTEC cultured under normal and diseased conditions representing a spectrum of in vivo disease severity from early inflammation, experienced in multiple initial kidney disease states, through to hypoxia, frequently seen in late stage chronic kidney disease (CKD) due to fibrosis and vascular compromise. We demonstrate a rapid reproducible methodology for the purification of PTEC-derived exosomes, identify increased numbers of exosomes from disease-state cultures and identify differential expression levels of both known and unique miRNA and protein species from exosomes derived from different disease-culture conditions. The validity of our approach is supported by the identification of miRNA, proteins and pathways with known CKD associations, providing a rationale to further evaluate these novel and known pathways as targets for therapeutic intervention.

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3-CD56+) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56dim NK cell subset and particularly the CD56bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56bright NK cells (NKp46+ CD117+) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease.

Everyday conversation in dementia: a review of the literature to inform research and practice.

BACKGROUND: There has been increasing interest in dementia care in recent years, including how practitioners, service providers and society in general can help individuals to live well with the condition. An important aspect to this is provision of advice to ensure conversation partners effectively support the person with dementia in conversation. AIMS: To provide a descriptive review of the literature examining everyday conversation in dementia in order to inform practice and research. METHODS & PROCEDURES: This review used a method specifically developed for reviewing conversation analytic and related literature. A range of databases were searched using key words and explicitly described inclusion criteria leading to a final corpus of 50 titles. Using this qualitative methodology, each paper was examined and data extracted. The contribution of each of these is described and the implications for practice and research are outlined. MAIN CONTRIBUTION: This review examined studies into conversation in Alzheimer's disease, vascular dementia and Lewy body dementia, grouping these into: early influential studies; work drawing on positioning theory; studies using social and linguistic approaches; collaborative storytelling; formulaic language; studies specifically using conversation analysis; and conversation as a target for individualized therapy. In addition, more recent work examining primary progressive aphasia and behavioural variant frontotemporal dementia was explored. Overall, this review indicates that research examining conversation in natural settings provides a rich source of data to explore not just the challenges within conversation for those taking part, but also the skills retained by the person with dementia. An important aspect of this understanding is the notion that these skills relate not only to information exchange but also aspects of social interaction. The role of others in scaffolding the conversation abilities of the person with dementia and the potential of this for developing interventions are discussed. CONCLUSIONS & IMPLICATIONS: The review indicates that interventions targeting conversation in dementia are often advocated in the literature but currently such approaches remain to be systematically evaluated. In addition, many of the important insights arising from these studies have yet to inform multidisciplinary dementia care practice.

The Mechanisms of Human Renal Epithelial Cell Modulation of Autologous Dendritic Cell Phenotype and Function.

Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.

Multiple repair sequences in everyday conversations involving people with Parkinson's disease.

BACKGROUND: Features of dysarthria associated with Parkinson's disease (PD), such as low volume, variable rate of speech and increased pauses, impact speaker intelligibility. Those affected report restricted interactional participation, although this area is under explored. AIMS: To examine naturally occurring instances of problems with intelligibility that resulted in multiple attempts at repair in order to consider repair initiation strategies that might restrict or enhance participation. METHODS & PROCEDURES: Thirteen people with PD (PwPD) video-recorded over 10 h of informal conversation data in their home setting involving familiar conversation partners (CPs). Using a conversation analytic (CA) approach, and drawing on an existing typology of repair initiators (RIs) for everyday talk-in-interaction and their relative power to locate a turn's repairable element, the design and ordering of RIs used by CPs was addressed, alongside their local consequences. OUTCOMES & RESULTS: CPs tended to increase the specificity of their RIs in line with the existing typology, progressing from open class forms (e.g. 'mm?') to more specific forms (e.g. questions/partial repeats). Repeated open class repair initiators (OCRIs) were used where PD speakers' self-repair attempts provided limited information. Sometimes, however, specificity was increased too soon, before enough syntactic knowledge was gleaned, which resulted in an extended repair sequence. Where one OCRI followed another, the second always took a different form: lexically or in terms of prosodic/non-verbal features. RI forms not described in the existing typology were also identified, such as 'prompts to modify speech' (e.g. 'Speak louder') and repeating/rephrasing the original first pair part (e.g. question), and their effectiveness examined. CONCLUSIONS & IMPLICATIONS: First steps are presented towards the design of a communication intervention promoting the efficient resolution of repair to moderate social withdrawal and increase participation for this client group. Future research will need to explore the feasibility and acceptability of such a resource.

Human proximal tubule epithelial cells modulate autologous B-cell function.

BACKGROUND: Descriptions of inflammatory cells infiltrating the human kidney rarely mention B cells, other than in the specific scenario of transplantation. In these reports, B cells are localized almost exclusively within the kidney tubulointerstitium where they are ideally placed to interact with proximal tubule epithelial cells (PTEC). We have previously shown that activated PTEC down-modulate autologous T lymphocyte and dendritic cell function. In this report, we extend these prior studies to describe PTEC-B cell interactions. METHODS: Stimulated B cells were cultured in the absence or presence of activated autologous human PTEC and monitored for proliferation, surface antigen expression, cytokine secretion and antibody (Ab) production. RESULTS: PTEC decreased B cell proliferative responses, whilst B cells cultured in the presence of PTEC displayed decreased levels of CD27, a marker of plasma B cells and memory cells. Interestingly, autologous PTEC also significantly decreased the number of B cells secreting both IgG and IgM and overall levels of Ab production. Transwell studies demonstrated that this modulation was primarily contact-dependent, and blocking studies with anti-PD-L1 led to partial restoration in Ab production. Further blocking studies targeting soluble HLA-G (sHLA-G) and IDO, two other immunoinhibitory molecules also up-regulated in our activated PTEC, demonstrated minor restoration of Ab responses. DISCUSSION: We report, for the first time, that PTEC are also able to modulate autologous B-cell phenotype and function via complex contact-dependent (PD-L1), soluble (sHLA-G) and intracellular (IDO) factors. We hypothesize that such mechanisms may have evolved to maintain peripheral immune-homeostasis, especially within the inflammatory milieu that exists within many kidney diseases.

Fractalkine-CX3CR1-dependent recruitment and retention of human CD1c+ myeloid dendritic cells by in vitro-activated proximal tubular epithelial cells.

Chemokines play pivotal roles in tissue recruitment and retention of leukocytes, with CX3CR1 recently identified as a chemokine receptor that selectively targets mouse kidney dendritic cells (DCs). We have previously demonstrated increased tubulointerstitial recruitment of human transforming growth factor-ß (TGF-ß)-producing DCs in renal fibrosis and chronic kidney disease (CKD). However, little is known about the mechanism of human DC recruitment and retention within the renal interstitium. We identified CD1c+ DCs as the predominant source of profibrotic TGF-ß and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c+ DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon-γ and tumor necrosis factor-α induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c+ DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c+ DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF-ß-producing CD1c+ DCs are recruited and retained in the renal tubulointerstitium by PTEC-derived fractalkine. These cells are then positioned to play a role in the development of fibrosis and progression of chronic kidney disease.

Life story resources in dementia care: a review.

PURPOSE: Life story work has a relatively long tradition in the caring sciences and is recognised as an important component of dementia care and practice. However, to date, there has not been a review of accessible life story resources. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: Following a systematic approach to identification and inclusion, 11 life story resources were reviewed to ascertain areas of commonality and divergence between the materials. FINDINGS: The authors were able to group the analysis under eight areas and at the end of this process, it was uncertain if life story work is a formal staff intervention or an informal activity that people with dementia and their families could engage in. Resources also varied in terms of whether the life story information was organised in a chronological way, or with topics of interest/discussion or with a combination of both. Life story evaluation and its impact on the life of the person with dementia is in need of development. PRACTICAL IMPLICATIONS: Across the resources the authors identified four reasons to do life story work which the authors have named as: emotional connections; interactional connections; building new connections and practical care connections. SOCIAL IMPLICATIONS: There was limited guidance aimed at helping people with dementia to develop and compile their own life story. ORIGINALITY/VALUE: This paper provides new insights into the usefulness, future directions and content of life story resources in dementia care. It will be of interest to those in health and social care as well as people living with dementia.

Living with semantic dementia: a case study of one family's experience.

Semantic dementia is a variant of frontotemporal dementia and is a recently recognized diagnostic condition. There has been some research quantitatively examining care partner stress and burden in frontotemporal dementia. There are, however, few studies exploring the subjective experiences of family members caring for those with frontotemporal dementia. Increased knowledge of such experiences would allow service providers to tailor intervention, support, and information better. We used a case study design, with thematic narrative analysis applied to interview data, to describe the experiences of a wife and son caring for a husband/father with semantic dementia. Using this approach, we identified four themes: (a) living with routines, (b) policing and protecting, (c) making connections, and (d) being adaptive and flexible. Each of these themes were shared and extended, with the importance of routines in everyday life highlighted. The implications for policy, practice, and research are discussed.