Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges

Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody‐mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross‐disciplinary diagnostic approaches.     

Biology of sepsis: Its relevance to pediatric nephrology

Because of its multi-organ involvement, the syndrome of sepsis provides clinical challenges to a wide variety of health care providers. While multi-organ dysfunction triggered by sepsis requires general supportive critical care provided by intensivists, the impact of sepsis on renal function and the ability of renal replacement therapies to modulate its biologic consequences provide a significant opportunity for pediatric nephrologists and related care providers to impact outcomes. In this review, we aim to highlight newer areas of understanding of the pathobiology of sepsis with special emphasis on those aspects of particular interest to pediatric nephrology. As such, we aim to: (1) review the definition of sepsis and discuss advances in our mechanistic understanding of sepsis; (2) review current hypotheses regarding sepsis-induced acute kidney injury (AKI) and describe its epidemiology based on evolving definitions of AKI; (3) review the impact of renal failure on the immune system, highlighting the sepsis risk in this cohort and strategies that might minimize this risk; (4) review how renal replacement therapeutic strategies may impact sepsis-induced AKI outcomes. By focusing the review on these specific areas, we have omitted other important areas of the biology of sepsis and additional interactions with renal function from this discussion; however, we have aimed to provide a comprehensive list of references that provide contemporary reviews of these additional areas.     

Evaluation of safety and efficacy as an adjuvant for the chitosan-based vaccine delivery vehicle ViscoGel in a single-blind randomised Phase I/IIa clinical trial

ViscoGel, a chitosan-based hydrogel, has earlier been shown to improve humoral and cell-mediated immune responses in mice. In this study, a Phase I/IIa clinical trial was conducted to primarily evaluate safety and secondarily to study the effects of ViscoGel in combination with a model vaccine, Act-HIB to Haemophilus influenzae type b, administered as a single intramuscular injection. Healthy volunteers of both sexes, ages 22–50 and not previously vaccinated to HIB, were recruited. The trial had two phases. In Phase A, three ascending dose levels of ViscoGel (25, 50 and 75 mg) were evaluated for safety in 3 × 10 subjects. Phase B had a single-blind, randomised, parallel-group design evaluating safety and efficacy in five groups, 20 subjects/group, comparing vaccination with 0.2 μg or 2 μg Act-HIB alone or combined with ViscoGel (50 mg) and one group receiving the standard Act-HIB dose (10 μg). No safety or tolerability concerns were identified. Local, transient reactions at the injection site were the most common adverse events. These were more frequent in groups receiving Act-HIB + ViscoGel, while other AEs were recorded at similar frequency in Act-HIB and Act-HIB + ViscoGel groups. Efficacy was evaluated by measuring serum anti-HIB antibodies and cellular responses in peripheral blood mononuclear cells (PBMC). There was a large variation in baseline anti-HIB antibody titres and no adjuvant effect was observed on the anti-HIB antibody production in groups vaccinated with Act-HIB + ViscoGel. ELISpot analyses revealed increased interferon-γ (IFN-γ) responses to Act-HIB in PBMCs from subjects vaccinated with Act-HIB in combination with ViscoGel, compared to groups receiving Act-HIB alone. Moreover, ViscoGel counteracted an inhibitory effect of Act-HIB vaccination on the IFN-γ response to both the vaccine itself and an irrelevant influenza antigen. In summary, ViscoGel was found to be safe and well-tolerated, supporting further examination of ViscoGel as a new innovative vehicle for vaccine development.     

Development of a transmission-blocking malaria vaccine: Progress,challenges, and the path forward

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.     

The association of PTSD with physical and mental health functioning and disability (VA Cooperative Study #569: the course and consequences of posttraumatic stress disorder in Vietnam-era Veteran twins)

Purpose

To assess the relationship of posttraumatic stress disorder (PTSD) with health functioning and disability in Vietnam-era Veterans.

Methods

A cross-sectional study of functioning and disability in male Vietnam-era Veteran twins. PTSD was measured by the Composite International Diagnostic Interview; health functioning and disability were assessed using the Veterans RAND 36-Item Health Survey (VR-36) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). All data collection took place between 2010 and 2012.

Results

Average age of the 5,574 participating Veterans (2,102 Vietnam theater and 3,472 non-theater) was 61.0 years. Veterans with PTSD had poorer health functioning across all domains of VR-36 and increased disability for all subscales of WHODAS 2.0 (all p < .001) compared with Veterans without PTSD. Veterans with PTSD were in poorer overall health on the VR-36 physical composite summary (PCS) (effect size = 0.31 in theater and 0.47 in non-theater Veterans; p < .001 for both) and mental composite summary (MCS) (effect size = 0.99 in theater and 0.78 in non-theater Veterans; p < .001 for both) and had increased disability on the WHODAS 2.0 summary score (effect size = 1.02 in theater and 0.96 in non-theater Veterans; p < .001 for both). Combat exposure, independent of PTSD status, was associated with lower PCS and MCS scores and increased disability (all p < .05, for trend). Within-pair analyses in twins discordant for PTSD produced consistent findings.

Conclusions

Vietnam-era Veterans with PTSD have diminished functioning and increased disability. The poor functional status of aging combat-exposed Veterans is of particular concern.     

Sex differences in symptomatology of psychosis-risk patients and in prediction of psychosis

Archives of Women's Mental Health - Sex differences may be important for understanding underlying pathophysiological mechanisms and developing effective preventions and treatments of mental...     

Functional conservation of suppressors of cytokine signaling proteins between teleosts and mammals: Atlantic salmon SOCS1 binds to JAK/STAT family members and suppresses type I and II IFN signaling

Suppressor of cytokine signaling (SOCS) proteins are crucially involved in the control of inflammatory responses through their impact on various signaling pathways including the JAK/STAT pathway. Although all SOCS protein family members are identified in teleost fish, their functional properties in non-mammalian vertebrates have not been extensively studied. To gain further insight into SOCS functions in bony fish, we have identified and characterized the Atlantic salmon (Salmo salar) SOCS1, SOCS2 and CISH genes. These genes exhibited sequence conservation with their mammalian counterparts and they were ubiquitously expressed. SOCS1 in mammalian species has been recognized as a key negative regulator of interferon (IFN) signaling and recent data for the two model fish Tetraodon (Tetraodon nigroviridis) and zebrafish (Danio rerio) suggest that these functions are conserved from teleost to mammals. In agreement with this we here demonstrate a strong negative regulatory activity of salmon SOCS1 on type I and type II IFN signaling, while SOCS2a and b and CISH only moderately affected IFN responses. SOCS1 also inhibited IFNγ-induced nuclear localization of STAT1 and a direct interaction between SOCS1 and STAT1 and between SOCS1 and the Tyk2 kinase was found. Using SOCS1 mutants lacking either the KIR domain or the ESS, SH2 and SOCS box domains showed that all domains affected the ability of SOCS1 to inhibit IFN-mediated signaling. These results are the first to demonstrate that SOCS1 is a potent inhibitor of IFN-mediated JAK-STAT signaling in teleost fish.