Abstract
Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objectives of this brief review are to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors, and inflammasomes in hypertension.
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Introduction
As recently reviewed [1–4], the importance of immunity and inflammation in hypertension and vascular disease has been appreciated for decades, yet progress has been slowed by limited experimental tools and conflicting results. Recently, with the advent of more robust experimental methods, significant progress has been made to elucidate the mechanisms linking inflammation and immunity to hypertension and cardiovascular disease. This review focuses upon recent experimental observations that may provide therapeutic targets.
Novel Immune Cell Subtypes Associated with the Development of Hypertension
Tregs and Th17 Cells
Experimental studies have focused upon the pathophysiological role of individual T cell subsets. Specific experimentation is elucidating the functions of two T cell subtypes distinct from the classical Th1 and Th2 paradigm—regulatory T cells (Tregs) and Th17 cells. The development, differentiation, and plasticity of these cell types are still under intense scrutiny among immunologists, but many researchers hypothesize therapeutic benefit for inflammatory disorders by altering the dynamics of Tregs and Th17 cells. In the past few years, studies have shown that Tregs attenuate hypertension and target organ damage, while Th17 cells exacerbate the pathology.
Regulatory T cells are characterized by high expression of the transcription factor forkhead box P3 (FOXP3) and the ability to suppress inflammatory signaling of immune and non-immune cells [5]. Tregs are essential for immunological self-tolerance, and deficiency of this cell type leads to autoimmune disease [6]. Tregs are touted as a possible therapy to quell the abhorrent inflammatory milieu thought to mediate target organ damage in many hypertensive models. Many types of Tregs have been described according to cell surface marker expression and/or cytokine profile in the human immune system (CD8+ Tregs, Tr1, natural killer Tregs, etc.) [7]; however, the main focus in the field of hypertension has been on natural Tregs, or CD4+CD25+FOXP3+ T lymphocytes. The mechanisms by which Tregs suppress inflammatory signaling continue to be elucidated, although it is widely thought that IL-10 and TGFβ play an important role in Treg-mediated immunosuppression [8].
Th17 cells are a recently described subset of T cells characterized by the expression of the master transcription factor retinoic acid-related orphan receptor (ROR)γt and by the production of interleukin 17 (IL-17) [9]. In contrast to the anti-inflammatory role of Tregs, Th17 cells are pro-inflammatory and exacerbate tissue damage and disease in conditions of chronic inflammation and autoimmunity [10]. This appears to be the case in hypertensive pathology as well, and blunting Th17 signaling may alleviate the inflammation associated with hypertension and target organ damage. For instance, the consequences of angiotensin II (AngII) infusion in mice—hypertension, vascular dysfunction, vascular inflammation, oxidative stress, aortic stiffening, and collagen deposition—are attenuated in IL-17a null mice (IL-17A−/−) [11, 12]. Moreover, administration of recombinant IL-17 in C57BL/6 mice decreases NO-dependent vascular relaxation via Rho-kinase signaling and causes hypertension [13••]. Similarly, IL-17 has been demonstrated to have deleterious cardiovascular effects in rodent models of deoxycorticosterone acetate (DOCA)-salt hypertension [14] and preeclampsia [15].
In contrast, Tregs are proposed to be protective. AngII-induced hypertension and endothelium-dependent vascular dysfunction in mice are attenuated by adoptive transfer of Tregs, possibly by reducing oxidative stress and/or increasing nitric oxide bioavailability in the vasculature [16, 17]. Additionally, in vitro studies showed that incubating resistance vessels with culture media from activated Tregs restored endothelium-dependent vasodilation and reduced vascular NADPH oxidase activity via an IL-10 dependent pathway [18]. Tregs have also been implicated in the protection from hypertension experienced by females, which has been attributed to sex-specific hormones [19]. Sex hormones have been shown to modulate immune function [20], and recent studies have investigated sex-dependent differences in immune system characteristics. For instance, in spontaneously hypertensive rats (SHR), Tregs represent a greater percentage of infiltrating T cells in the kidneys of female rats compared to males [21]. This finding correlates with increased number of IL-10+ renal cells and lower IL-17+ cells in female SHR compared to males [22•], suggesting that Tregs may mediate the protection against hypertension in females. Moreover, transaortic constriction in the mouse results in hypertension, infiltration of immune cells in the heart, and cardiac fibrosis. Adoptive transfer of Tregs in this model has no effect on blood pressure but significantly blunts accumulation of immune cells in the heart, blunts cardiac hypertrophy, and attenuates left ventricular fibrosis [23]. Other studies have shown blood pressure-independent protection via Tregs and damage via Th17 cells of cardiovascular organs, suggesting a greater role for Tregs and Th17 cells in cardiovascular disease.
Data regarding the role of Tregs and Th17 cells in human hypertension are sparse, although an intriguing study by Kleinewietfeld et al. [24••] showed that differentiation of naïve human T cells to the Th17 phenotype in culture is greatly enhanced when in the presence of elevated concentrations of NaCl [24••]. Due to high levels of NaCl consumption in developed countries and the argued correlation between high salt intake and increased blood pressure, the direct effect of NaCl on T cell differentiation could have drastic effects on organ damage and blood pressure regulation. Ultimately, much work needs to be done to fully appreciate the role of Tregs and Th17 cells in hypertension and target organ damage. Studies thus far indicate that understanding the mechanisms by which these cells elicit their phenotypic effects may lead to novel therapeutic targets for the treatment of hypertension.
Dendritic Cells
Dendritic cells (DCs) are bone marrow-derived, professional antigen-presenting cells (APC) that play a key role as modulators of the inflammatory response. Four subsets of DCs have been characterized, including classical DCs (cDCs), plasmacytoid DCs (pDCs), monocyte-derived inflammatory DCs (Mo-DCs), and Langerhans cells [25, 26]. DCs form a dense network in most human and animal tissues, including areas important in the regulation of blood pressure, such as arteries [27], kidneys [28], and brain [29]. These immature, resident DCs are thought to maintain tolerance and organ homeostasis by patrolling the environment for self- and non-self-antigens. In pathological conditions such as atherosclerosis, chronic kidney disease, or pulmonary hypertension, DCs become activated and induce activation of T lymphocytes.
Immature or precursor DCs can also be found in the bloodstream, surveying for potential antigens. The amount of circulating precursor DCs is indicative of the immune status of the organism, and decreased blood precursor DC levels have been reported in inflammation-related cardiovascular disorders. Reduced circulating precursor DC numbers in patients with atherosclerosis, myocardial infarction, or stage 3 chronic kidney disease have been associated with enhanced activation and recruitment of mature DCs in vascular lesions, infarcted areas, or renal tissue [30–32]. Once in the tissue, DCs act as mediators of cardiovascular disease. These reports highlight the potential use of circulating precursor DCs as new cardiovascular biomarkers to predict the development of cardiovascular disease.
In experimental hypertension, interesting new research has shown that AngII-induced superoxide production in DCs is associated with the accumulation of products of free radical-mediated lipid peroxidation, known as isoketals, in these cells. Isoketals can cross-link lysine residues on proteins, rendering them immunogenic. In turn, DCs present these modified proteins to T lymphocytes, triggering T cell activation and hypertension [33••]. The use of isoketal scavengers in mice prevented activation and immunogenecity of DCs and attenuated hypertension in response to a subpressor dose of AngII. These results identify isoketal scavengers as a new potential therapeutic approach to the prevention of hypertension in humans. These data, together with reports by Nahmod et al. [34] on the importance of AngII receptor type 1 (AT1) on DCs’ differentiation and functionality, emphasize the role of DCs on the development of AngII-induced hypertension.
Recent reports also highlight the role of the mineralocorticoids aldosterone and DOCA, well-known inducers of hypertension, on promoting DC-induced polarization of T cells towards the pro-inflammatory phenotype Th17 [35]. As explained above, Th17 cells have been strongly implicated in the development of hypertension. In these studies, treatment with the mineralocorticoid receptor inhibitors spironolactone and epleronone prevented the stimulatory effects of aldosterone on DCs and inhibited polarization of T cells into Th17 cells [35]. These studies suggest the potential use of mineralocorticoid receptor inhibitors as immunomodulator therapy to treat hypertension.
Naïve T cells require two signals for activation: interaction of the T cell receptor with the processed peptide presented by the APC and simultaneous interaction of additional receptors on the T cell surface with B7 ligands on the APC surface. Due to this required dual activation, inhibition of the B7-mediated T cell activation pathways has also been proposed as new therapy for the treatment of hypertension. Vinh et al. [36] demonstrated that in an experimental model of hypertension, blockade of B7-dependent co-stimulation by CTLA4-Ig reduces the development of hypertension in response to AngII and DOCA, opening a new promising avenue for the development of therapies against the disease. In short, further research is required to fully understand the role of DCs in hypertension, especially regarding the role of these cells in other kinds of hypertension, such as salt-sensitive hypertension.
Immunosenescent CD8+ Cells
Chronic antigen stimulation leads to gradual accumulation of late differentiated CD8+ T cells, characterized by critically shortened telomeres, loss of the costimulatory receptor CD28, gain of CD57 receptor expression, and increased production of inflammatory cytokines and chemokines [37]. These T cells have been traditionally called immunosenescent, but, contrary to their name, CD8+CD28−CD57+ T cells maintain the ability to proliferate under certain activation conditions [37]. Accumulation of these cells occurs with aging and in chronic inflammatory states such as cancer or autoimmune diseases. Given the role that inflammation plays in hypertension, it has also been proposed that these cells could play a role in the development of disease. Youn et al. [38••] demonstrated that hypertensive patients have an increased fraction of circulating immunosenescent CD8+ T cells and elevated circulating levels of C-X-C chemokine receptor type 3 (CXCR3) chemokines and serum granzyme B compared to healthy, age-matched control subjects. CXCR3 chemokines are well-known tissue-homing chemokines for T cells. On the other hand, granzyme B is a protease used by cytotoxic cells to induce cell death in target cells, and it is elevated during T cell-driven inflammation. Of note, CD8+CD28−CD57+ T cells are known to be highly cytotoxic. Although this study has some limitations, this report is the first implicating the involvement of T cells in human hypertension and specially highlights the importance of immunosenescent CD8+ T cells in the disease.
The Role of Cytokines in the Development of Hypertension
Recent attention has been focused on exploring the pathways and inflammatory mediators that immune cells use to drive high blood pressure and end-organ damage. When immune cells become activated and/or are recruited to a target organ, they produce cytokines that determine the local inflammatory response. Chemokines, special kinds of cytokines, are chemoattractants that direct migration of immune cells into tissues. Some of the inflammatory cytokines and chemokines that have been studied for their involvement in hypertension are TNF-α, IL-17, MCP-1, and IL-6.
Contributions of TNF-α to the development of high blood pressure have been demonstrated by pharmacological or genetic approaches in animal models of AngII-induced hypertension, lupus, metabolic syndrome, and preeclampsia, as reviewed by Ramseyer and Garvin [39]. In these cases, blockade of the TNF-α pathway led to decreased blood pressure and inflammation. However, contrasting results were reported in other models of hypertension like DOCA-salt hypertension or a human Ang/renin double transgenic rat model of AngII hypertension [39]. These opposite observations may be explained by the different type of TNF-α receptor that is activated in each model. To date, two different TNF-α receptors have been described: TNFR1 and TNFR2, but complete understanding of their functions is still lacking. Most pro-inflammatory effects of TNF-α are associated with activation of TNFR1, and, in humans, high serum TNFR1 levels strongly correlate with diseases associated with hypertension, like end-stage renal disease and type 2 diabetes [40]. Other reports, however, indicate that genetic deletion of TNFR1 leads to increased blood pressure in response to AngII [41]. On the other hand, some reports link TNFR2 activation to increased vascular inflammation [42], while others suggest that it has beneficial roles in the cardiovascular system [43]. It is clear from these contradictory reports that further investigation of the role of TNF-α and its receptors in hypertension is needed to develop better therapies.
In recent years, the pro-inflammatory cytokine IL-17 has been implicated in the development of hypertension. This cytokine is produced by Th17 cells, macrophages, dendritic cells, and natural killer cells in response to immune activation [44]. Elevated IL-17 correlated with hypertension in subjects with type 2 diabetes [11] and in patients with preeclampsia and lupus [45], diseases associated with elevated blood pressure. Madhur et al. [11] reported that IL-17 is required for the maintenance of AngII-induced hypertension and vascular dysfunction. Another group recently demonstrated that this effect of IL-17 on vascular function is mediated by promoting NOS3 phosphorylation, thus decreasing enzyme activity and NO production in endothelial cells [13••]. This cytokine could also be important in salt-sensitive hypertension, since recent studies indicate that naïve T cells increase expression of serum glucocorticoid kinase 1 (SGK1; a known salt-sensor protein) and polarize to Th17 cell phenotype in the presence of high salt. These studies demonstrate that SGK1 is critical for the induction of Th17 cells and could hint to a mechanism by which high salt may trigger Th17 development and IL-17 production and promote tissue inflammation [46••].
By activating the CCR2 receptor, chemokine MCP-1 (also known as CCL2) leads to the activation and migration of monocytes and leukocytes to sites of inflammation. Production of MCP-1 can be stimulated by AngII [47] and endothelin-1 [48], fundamental players in the development of hypertension and end-organ damage. Moreover, the use of Ang receptor blockers reduces MCP-1 levels both in experimental models and in hypertensive patients [49]. In addition, genetic deletion of the MCP-1 axis or blockade of CCR2 in experimental models decreases blood pressure and reduces vascular and renal inflammation [50, 51]. These results highlight the potential of MCP-1 axis inhibition for treating hypertension; however, in-depth clinical studies are still needed.
Levels of the pro-inflammatory cytokine IL-6 are also elevated in hypertensive conditions. Studies by Brands et al. [52] demonstrated that IL-6 is fundamental for the development of AngII-induced hypertension and that activation of the JAK/STAT3 pathway by IL-6 plays a key role in the disease. Moreover, a human study further confirmed these results by showing that plasma levels of IL-6 increase in response to acute AngII infusion and that these levels are exaggerated in hypertensive patients [53•]. IL-6 is also elevated in pulmonary hypertension, and anti-IL-6 antibody therapy has been successfully used in a one-patient clinical trial in Japan [54], indicating the potential therapeutic value of targeting IL-6.
Although CD40L is not considered a cytokine, it is included in this section because of its powerful pro-inflammatory effects. CD40L is part of the TNF superfamily and acts by promoting cytokine and chemokine release. It is derived from activated platelets and has been implicated in thrombosis [55]. Recent research also suggests that AngII promotes and augments the inflammatory activity of the CD40/CD40L system in human vascular cells [56] and that genetic deletion of CD40L improves endothelial dysfunction and decreases aortic inflammation and oxidative stress [57•]. These reports suggest that CD40L mediates many deleterious effects of AngII in the vasculature. In addition, soluble CD40L (sCD40L) is elevated in the plasma of hypertensive patients and significantly decreased after antihypertensive treatment [58]; also, non-dipper hypertensive patients (at increased risk of cardiovascular events) present increased CD40L levels [59]. Based on these reports, CD40L could be a valuable biomarker of cardiovascular disease and a potential therapeutic target.
Toll-Like Receptors: Controllers of the Adaptive Immune Response in Hypertensive Conditions
The involvement of the innate immune response has emerged as an important determinant of hypertension and end-organ damage. Contrary to what was originally believed, the innate immune system not only responds to exogenous pathogens, but it can also be activated by endogenous molecules released by stressed, damaged, or necrotic cells [60]. These molecules, known as damage-associated molecular patterns (DAMPs), are important inflammatory mediators [61]. Examples of DAMPs include high mobility group box 1 (HMGB1), heat shock proteins 60 and 70, AngII, IL-1α, uric acid, DNA fragments, mitochondrial content, HDL, and oxidized LDL [62•, 63]. Interestingly, many of these DAMPs are known to be present in cardiovascular diseases such as atherosclerosis [64], diabetes [65], pulmonary hypertension [66], essential hypertension [67], and preeclampsia [68].
Toll-like receptors (TLRs) are a conserved family of receptors that trigger pro-inflammatory signaling cascades in response to either microbial structures or DAMPs released by injured tissues [62•]. These receptors have a fundamental role in the innate immune response. Eleven different TLRs have been described in humans and thirteen in mice (TLR1-13) [69]. Different signaling cascades are activated by TLRs depending on adaptor protein binding [70]. Examples of adaptor proteins include myeloid differentiation factor 88 (MyD88), MyD88-adapter-like (Mal), IL-1 receptor associated kinase-4 (IRAK4), and TIR-containing adaptor molecule (TICAM).
Recent studies suggest that the innate immune system may be the first step in the pathogenesis of hypertension and that TLRs may be the molecular link between the innate and adaptive immune responses during cardiovascular disease. In fact, expression of TLRs has been described in blood vessels [69], brain [71], renal tubules, podocytes, mesangial cells [65], T lymphocytes, macrophages, and dendritic cells [69, 72]; all key players in the development and maintenance of hypertension. In recent years, TLRs have been implicated in preeclampsia (TLR2, TLR3, TLR4, and TLR9 [73–75]); programming of vascular dysfunction (TLR4 [76]); hypertension induced by AngII (TLR2 and/or TLR4 [77, 78]), obesity (TLR4 [79]), or l-NAME (TLR4, [80]); atherosclerosis (TLR2 [81]); pulmonary hypertension (TLR4 [66]); diabetic nephropathy (mostly TLR4 but also TLR2 [65]); and ischemia-reperfusion renal injury (TLR2 and/or TLR4 [82]). In addition, TLR7 and TLR9 have been shown to be involved in the inflammation typical of lupus [83], a disease also associated to hypertension.
In light of the involvement of TLRs in cardiovascular disease, several novel therapies designed to target these receptors are in the works [84]. By targeting TLRs, modulation of the inflammatory cascade may be achieved at an earlier point and control disease more effectively. The number of TLR antagonists is still very limited, however, and further preclinical research is needed. A powerful anti-TLR2 antibody has been reported as effective in reducing the myocardial infarct area in mouse and pig models of ischemia/reperfusion [85, 86] and to diminish and stabilize atherosclerotic lesions in a mouse model [87]. TLR4-antagonists RsLPS and CXR-526 showed promising results against the development of atherosclerotic plaques [88] and significantly decreased signs of kidney injury in a mouse model of type 1 diabetes [89], respectively. Moreover, treatment with antibodies against TLR4 is efficient in ameliorating hypertension in DOCA-salt and SHR rat models [90, 91]. Additionally, dual blockade of TLR7/9 decreased inflammation in a model of lupus [83]. Alternative approaches, like targeting the adaptor proteins or increasing ubiquitination of TLRs [84], are also being studied.
Overall, these studies support the involvement of TLRs in the development of hypertension and other related cardiovascular diseases and highlight these receptors as attractive targets for potential new therapies. Despite the existence of several TLR antagonists, further understanding of the roles of TLRs and how they vary in different cardiovascular diseases is needed in order to develop more TLR-targeting therapeutic options.
The Role of Inflammasomes in Hypertension
The nucleotide-binding oligomerization domain (Nod)-like receptor containing pyrin domain 3 (NLRP3, also known as NALP3 or cryopyrin) inflammasome is the most characterized member of the nucleotide-binding domain leucine-rich repeat (NLR) family of pattern recognition receptors (PRRs). Activation of the NLRP3 inflammasome signifies cleavage and activation of a subclass of inflammatory caspases that are responsible for the maturation of inactive pro-inflammatory cytokine precursors like pro-IL-1β or pro-IL-18. NLRP3 inflammasome formation controls the innate immune system activation in response to a wide range of danger signals including pathogen-associated molecular patterns (PAMPs) and DAMPs derived from disease and infection.
With 23 NLR genes identified, there exist other types of caspase-processing inflammasomes, including NLRP1, NLRC4, and AIM2. NLRP1 was the first discovered inflammasome demonstrated to process both caspase-5 and caspase-1 and is primarily activated by bacterial cell wall component muramyl dipeptide (MDP) and Bacillus anthracis lethal toxin [92, 93]. NLRC4 inflammasomes sense various gram-negative bacteria conserved proteins like flagellin, rod, and needle [94, 95], while AIM2 inflammasomes respond to foreign nucleic acids and double-stranded DNA [96]. The NLRP3 inflammasome has gained much attention over recent years due to its growing role in the sterile inflammatory response to DAMPs associated with a number of chronic degenerative diseases [97, 98]. Activation by this diverse range of danger signals results in a cytosolic multiprotein complex formed by the oligomerization of the NLRP3 sensory protein, the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC), and the cysteine protease caspase-1, causing the maturation of pro-inflammatory cytokines IL-1β and IL-18, thereby contributing to very early initiation of the immune response.
Very recent and exciting literature suggests an important role for NLRP3 inflammasomes in humans and animal models of kidney disease and hypertension. NLRP3 inflammasome involvement has been reported in glomerular and tubulointerstitial injury, where NLRP3 mRNA is significantly increased in renal biopsies of patients with various types of nondiabetic kidney disease, including acute tubular necrosis, focal segmental glomerulosclerosis, and hypertensive nephrosclerosis [99••]. In NLRP3 and ASC-deficient mice, glomerular injury, renal leukocyte infiltration, and T cell activation associated with nephrotoxic serum nephritis was attenuated [100••]. Furthermore, the inflammasome has been shown to contribute to IgA nephropathy, hyperhomocysteinemia-induced glomerular sclerosis, and ischemia-reperfusion injury [101–103]. In mouse models of hypertension, studies have demonstrated protective effects of inflammasome inhibition in the two-kidney, one clip (2K1C) model, where NLRP3 or ASC deficiency prevents blood pressure elevation and lowers plasma renin activity [104]. Additionally, in murine ATP-induced hypertension, ATP infusion resulted in increased salt-sensitive hypertension, caspase-1 activity, IL-1β production, and CD43+ T cell infiltration in the renal medulla [105]. Administration of caspase-1 inhibitor WEHD, however, blocked ATP-induced hypertension, reduced sodium retention, and blunted inflammasome activation and the production of IL-1β. In humans, an intronic 42 base pair variable number of tandem repeat (VNTR) polymorphism in the CIAS1 gene that encodes for NLRP3 has been linked to essential hypertension susceptibility [106••]. Interestingly, the CIAS1 gene is part of the CATERPILLER gene family, which also contains PYPAF5 that encodes the AngII/vasopressin receptor (AVR) implicated in salt-sensitive hypertension in the Dahl SS model [107]. Patients with pulmonary arterial hypertension demonstrated increased NLRP3 inflammasome complex formation and caspase-1 activation in purified monocytes compared to control subjects and also had significantly elevated IL-1β and IL-6 in the serum [108]. Superoxide scavenging experiments suggest that these inflammasome-activating effects may be due to an oxidant/antioxidant imbalance [109]. Together, these animal and human data strongly implicate an important contribution of the NLRP3 inflammasome in the development of hypertension and may potentially serve as an early disease biomarker and therapeutic target.
Conclusions
Innate and adaptive immunity play a significant role in the pathogenesis of hypertension. Specific immune cell types, cytokines, toll-like receptors, and components of inflammasomes all pose novel targets for antihypertensive therapy. These targets are summarized in Table 1. Further research will remain to elucidate the interrelationship and common mediators of these immune mechanisms.
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This manuscript was partially funded by grants DK96859 and HL116264 to DLM and NIH T32 DK007545 to CDM.
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Nathan P. Rudemiller declares that he has no conflict of interest.
Justine M. Abais, Carmen De Miguel and David L. Mattson report grants from the National Institutes of Health.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action
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De Miguel, C., Rudemiller, N.P., Abais, J.M. et al. Inflammation and Hypertension: New Understandings and Potential Therapeutic Targets. Curr Hypertens Rep 17, 507 (2015). https://doi.org/10.1007/s11906-014-0507-z
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DOI: https://doi.org/10.1007/s11906-014-0507-z