Spirituality in the natural sciences and nursing: an interdisciplinary perspective.

The Big Bang theory, a widely accepted theory of the origin of the universe, states that the universe was created between ten to twenty billion years ago from a cosmic explosion. Charles Darwin, a 19th century English naturalist, convinced the scientific community through his work that life evolved by natural selection over three and a half million years ago rather than through the influence of a Supreme Being or creator. Although there has been scientific data to support the claims of natural selection, there still remain many unanswered questions suggesting that other mechanisms contributed to the evolution of life. These unresolved findings greatly influenced mysticism and the development of the theological argument, which suggest the existence of a supreme being (God), who is believe to be an omnipotent healer, comforter, provider of salvation, and the center of mysticism spirituality. There has been consistent use of spiritual practices to address health concerns by individuals for thousands of years. There is increasing data that supports the implementation of spirituality in nursing for client care to enhance health outcome and patient wellbeing. Incorporating spiritual care into practice is an integral dimension of holistic care that is the crux of nursing practice in the 21st century. Holistic care of clients requires that nurses use the nursing process to implement spiritual care in practice.     

Depressive symptoms in patients with obstructive sleep apnea: biological mechanistic pathways

This study examined the association between depressive symptoms, as well as depressive symptom dimensions, and three candidate biological pathways linking them to Obstructive sleep apnea (OSA): (1) inflammation; (2) circulating leptin; and (3) intermittent hypoxemia. Participants included 181 obese adults with moderate-to-severe OSA enrolled in the Cardiovascular Consequences of Sleep Apnea (COSA) trial. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II). We assessed inflammation using C-reactive protein levels (CRP), circulating leptin by radioimmunoassay using a double antibody/PEG assay, and intermittent hypoxemia by the percentage of sleep time each patient had below 90% oxyhemoglobin saturation. We found no significant associations between BDI-II total or cognitive scores and CRP, leptin, or percentage of sleep time below 90% oxyhemoglobin saturation after controlling for relevant confounding factors. Somatic symptoms, however, were positively associated with percentage of sleep time below 90% saturation (β = 0.202, P = 0.032), but not with CRP or circulating leptin in adjusted models. Another significant predictor of depressive symptoms included sleep efficiency (β_{BDI Total} = ?0.230, P = 0.003; β_cognitive = ?0.173, P = 0.030 (β_somatic = -0.255, P = 0.001). In patients with moderate-to-severe OSA, intermittent hypoxia may play a role in somatic rather than cognitive or total depressive symptoms.     

Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells

Although mature dendritic cells (DCs) are potent initiators of adaptive immune response, immature steady-state DCs contribute to immune tolerance. In this study, we show that ex vivo splenic DCs are capable of inducing conversion of naïve CD4⁺ T cells to adaptive Foxp3⁺CD4⁺ regulatory T cells (aTreg) in the presence of TGF-β. In particular, when compared with splenic CD8α⁻ DCs, the CD8α⁺ DC subset were superior in inducing higher frequencies of conversion. This was not attributable to the difference in basal level of costimulation, because deficiency of CD40 or CD80/86 signaling did not diminish the differential induction of Foxp3. Conversion was regulated by DC maturation status. Further insights into the molecular mechanisms of conversion were gained by analyzing the contribution of several costimulatory and coinhibitory receptors. Costimulatory signals through GITR suppressed conversion, whereas coinhibitory signaling via programmed death 1 ligand (PD-L1) but not PD-L2 was required for conversion. Ex vivo PD-L1^−/− DCs failed to support Foxp3 induction in the presence of TGF-β. In vivo blocking PD-L1 signaling abolished conversion in a tumor-induced aTreg conversion model. Collectively, this study highlights the cellular and molecular parameters that might be exploited to control the de novo generation of aTregs and peripheral tolerance.     

Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer.T-cell activation requires engagement with antigen-presenting cells (APCs) that present the cognate peptide on MHC molecules. Antigen recognition is regulated by cosignaling ligands and receptors, whose integrated signaling determines the outcome of T-cell activation, differentiation, and function (1). The B7 family of coreceptors belongs to the Ig superfamily, consisting of stimulatory receptors such as CD28 and inducible T-cell costimulator (ICOS), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed death 1 (PD-1) coinhibitory receptors, and B7-H3 and B7-H4 ligands, whose receptors have yet to be identified (1, 2). Together with additional inhibitory molecules such as T-cell immunoglobulin domain and mucin domain 3 (Tim-3), lymphocyte-activation gene 3 (LAG3), and B- and T-lymphocyte attenuator (BTLA), these immune-checkpoint proteins play critical roles in maintaining peripheral tolerance and controlling autoimmunity.VISTA is a newly identified Ig domain-containing immune-checkpoint molecule that directly suppresses T-cell activation in vitro and in vivo (3, 4). The human and murine VISTA proteins share 90% identity and display similar expression patterns (5). VISTA is constitutively expressed within the hematopoietic compartment, with the highest expression level on myeloid cells and a lower level on CD4⁺, CD8⁺ T cells, and Foxp3⁺CD4⁺ regulatory T cells. A soluble VISTA-Ig protein that contains the extracellular domain fused with Ig-crystalizable fragment (Fc) or full-length VISTA expressed on APCs acts as a ligand to suppress T-cell proliferation and cytokine production (3). In addition, VISTA might function as an inhibitory receptor on T cells to suppress their activation (6). VISTA-specific monoclonal antibody (mAb) enhances disease severity in the experimental autoimmune encephalomyelitis (EAE) model, as well as boosts antitumor immunity in multiple murine tumor models (7).The regulatory functions of immune-checkpoints have been demonstrated using KO mice, which typically manifest loss of peripheral tolerance and heightened T-cell responses. For example, CTLA-4 KO mice die of young age because of overwhelming lymphoproliferative disease and inflammation (8, 9). PD-1 KO mice display genetic background-dependent late-onset autoimmune disease of either dilated cardiomyopathy or arthritis (10, 11). PD-1 binds to two ligands, PD-ligand 1 (L1) and PD-L2 (12, 13). Although neither PD-L1 nor PD-L2 KO mice develop overt organ-specific autoimmune disease, PD-L1 genetic deficiency exacerbates disease in the EAE model, as well as impairs fetomaternal tolerance (14, 15). These data suggest a critical role for PD-L1 in maintaining T-cell peripheral tolerance at tissue sites. In contrast, genetic disruption of other immune checkpoint ligands such as B7-H4 fail to display any significant alterations of T-cell responses in vivo, suggesting there is a hierarchy and potential redundancy among various immune-checkpoint regulators (16). In this context, it is important to note that the expression pattern of VISTA overlaps with multiple other immune-checkpoint regulators (3). It is therefore critical to determine whether VISTA exerts nonredundant immune regulatory functions.Studies have shown that several immune-checkpoints functionally synergize with each other (17–19). For example, the combined disruption of LAG3 and PD-1 genes results in lethal autoimmune diseases, whereas loss of either gene alone leads to subtle phenotypes (17). In addition, PD-1 functionally synergizes with TIM3 (18, 19). A combinatorial antibody-mediated blockade of both PD-1 and TIM3 results in optimal T-cell responses against cancer, as well as during chronic viral infection (18, 19). In the current study, we use KO mice to address whether VISTA synergizes with PD-1 in regulating T-cell responses. Our data establish that VISTA and the PD-1/PD-L1 pathways nonredundantly regulate T-cell activation and demonstrate the feasibility of concurrently targeting these two immune-checkpoints to enhance tumor-specific immune responses.