1. Introduction {#sec1}
===============

Primary Sjögren\'s syndrome (pSS) is an autoimmune disease with exocrine gland dysfunction and at least one-third of patients experience multiorgan involvement \[[@B1]\]. Furthermore, 5% of patients may develop lymphoma, mainly the mucosa-associated lymphoid tissue (MALT) non-Hodgkin lymphoma (NHL), which represents the most severe complication of the disease \[[@B2]\].

Histologically, pSS is characterized by extensive target tissue infiltration of lymphocytes, mainly represented in the salivary glands by T cells, predominantly CD4^+^T cells, but also CD8^+^T cells \[[@B3]\]. Although T cells predominate in mild lesions, B cells are the most represented cell subset in the advanced lesions, with a decreased percentage of macrophages and an increased percentage of dendritic cells \[[@B4]--[@B6]\]. Infiltrating lymphocytes are often organized into tertiary ectopic lymphoid structures, showing a network including specific segregated T- and B-cell zones, associated with follicular dendritic cells, with a specific glandular cytokine profile \[[@B7]\]. Despite the presence, and sometimes predominance, of T cells in salivary gland infiltrates, their pathogenic role in pSS remains to be elucidated.

CD4^+^T helper (Th) lymphocytes have been long known to be distributed into Th1 and Th2 cells, based on distinct cytokine patterns \[[@B8]\]. An imbalance between type 1 cytokine-producing Th1 cells and type 2 cytokine-producing Th2 cells has been considered as predisposing to autoimmunity. Historically, pSS was thought to be a Th1 driven disease due to the predominance of CD4^+^T lymphocytes and their products, namely, interferon-*γ* (IFN-*γ*), in target organs and peripheral blood (PB) of these patients. Inevitably, on the basis of*in vitro* and*in vivo* observations, the role of Th1 and Th2 cells in pSS has become contradictory. In the last decade, a number of Th cell lineages, including Th0, Th17, regulatory T (Treg), and follicular helper T (Tfh) cells, have been identified \[[@B9]\]. This challenged the long-standing paradigm of a Th1/Th2 immune response and prompted to identify their role in the pathogenesis of autoimmune diseases including pSS. In particular, Th17 cells were described and IL-17 was acknowledged as a prime representative of the new generation of proinflammatory cytokines \[[@B10]\]. Concomitantly, regulatory T (Treg) cells were identified as a unique population of Th cells that restrain excessive activation of effector lymphocytes \[[@B11]\].

Besides the role of different cell subsets in pSS pathogenesis, the impact of abnormal cytokine production, such as IL-6, IL-17, and BAFF, has also attracted considerable attention. In particular, it is a challenge to understand how the interaction between several interconnected networks of cytokines impact so many different cell populations, on one hand, and how the interplay of cytokine-producing T and B cells shifts the balance towards autoreactive T and B lymphocytes, on the other.

The ongoing progress in discovering lymphocyte subsets and the lengthening list of cytokines involved has further fuelled the debate on pSS pathogenesis ([Figure 1](#fig1){ref-type="fig"}). The main purpose of this review is to summarize and highlight the role of IL-17-producing T cells and Treg cells in pSS pathogenesis, offering the rationale for new therapeutic approaches in this disease.

2. Regulatory T Cells in pSS {#sec2}
============================

Treg cells were initially identified in mice and humans according to the high surface expression of the alpha chain of IL-2 receptor (IL-2R*α*, CD25) and the capability to prevent polyautoimmunity in an experimental animal model \[[@B11]\]. This cellular subset exerts suppressive activity towards autoreactive lymphocytes via either cell-cell contact or the release of soluble mediators including IL-10 and transforming growth factor *β* (TGF-*β*) \[[@B12]\]. The commitment of a naïve T lymphocyte towards a Treg phenotype is dependent of a peculiar cytokine microenvironment and of the expression of the forkhead box protein P3 (FoxP3) transcriptional factor, which ensures Treg suppressive function and represents to date the most specific Treg marker \[[@B13], [@B14]\]. Intriguingly, soluble mediators required for Treg commitment are also those which participate in the commitment of a pathogenic IL-17-producing T helper (Th) subset, the Th17 cells. In fact, TGF-*β* is required in both cases, but the concurrent presence or absence of IL-6 leads to the generation of either Th17 or Treg cells, respectively \[[@B15]\]. It is evident, therefore, that such a fine balance between these two cell subsets may be easily disturbed leading to a predominance of pathogenic cells and therefore to the development of autoimmunity. In this context, it has been demonstrated that a committed Treg cell can be turned into a Th17 cell in the presence of appropriate stimuli. An interesting study, employing a FoxP3 reporter mouse, revealed that the blockade of indoleamine 2,3-dioxygenase, a master regulator of self-tolerance, in the presence of IL-6 induced conversion of Treg into Th17-like cells in rodent tumor-draining lymph nodes \[[@B16]\].

As far as the role of Treg cells in pSS pathogenesis is concerned, ten studies have been published and the results are often controversial \[[@B17]--[@B26]\]. Therefore, similar to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), conclusive data are still lacking \[[@B27], [@B28]\] ([Table 1](#tab1){ref-type="table"}).

Such discrepancies may be explained at least in part by the different strategies employed to assess Treg cells over time. Generally, the approach of earlier studies was to enumerate the proportion of circulating Treg cells according to the high surface expression of CD25. Subsequently, however, the coexpression of FoxP3, the most specific marker of Treg cells, was also evaluated.

Five studies reported an overall reduction of PB CD25^high^Treg cells \[[@B18], [@B19], [@B22], [@B24], [@B26]\], but, of note, an association between this reduction and clinical or serological features was observed only in 2 studies. In detail, Liu et al. reported an inverse correlation between the percentage of Treg cells and C reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and immunoglobulin (Ig) G concentration \[[@B19]\]. Conversely, Szodoray et al. described that Treg cell reduction in the PB was more pronounced in patients with a milder clinical picture not presenting extraglandular manifestations \[[@B22]\].

In striking contrast, two studies reported an increase of circulating Treg cells in pSS, not associated, however, with any clinical or serological features \[[@B17], [@B23]\] and three described that PB CD4^+^CD25^high^ cell percentages were similar in pSS and controls \[[@B20], [@B21], [@B25]\].

Only two studies tried to correlate the disease activity with the percentage of peripheral Treg cells. In particular, we subdivided patients into two groups according to the EULAR Sjogren\'s syndrome disease activity index (ESSDAI) values: patients with ESSDAI ≤2, whose only manifestation of disease was a mild stable polyclonal hypergammaglobulinemia, were considered inactive, whereas patients with ESSDAI \>2 were classified as active \[[@B26]\]. We observed that the disease activity did not influence the number of circulating CD4^+^CD25^high^Treg cells. Similarly, another study defined clinical active disease as the presence of one or more glandular and extraglandular features recognized by the ESSDAI and the Sjögren syndrome disease activity index (SSDAI) with the exception of fatigue and serologic activity as the presence of increased serum viscosity, elevated IgG, IgM, IgA, or decreased levels of complements C3 and C4 \[[@B25]\]. No statistically significant differences in the frequency of CD4^+^CD25^high^FoxP3^+^ cells were found.

The apparently paradoxical increase as well as the normal values of circulating Treg cell percentages described in some studies deserves some consideration. The surface expression of CD25 in not limited to Treg cells but can be shared by recently activated lymphocytes \[[@B29]\]. In this setting, Han et al. observed that only a subgroup of CD25^high^ T cells coexpresses FoxP3 in RA patients \[[@B30]\]. Therefore, higher percentages of CD25^high^ T cells in RA patients may be due more likely to a contamination of recently activated cells rather than to an increase of real Treg cells. In line with this hypothesis, Sarigul et al. reported that, besides an increase of circulating CD25^high^ Treg cells in pSS, the proportion of FoxP3^+^ cells in the PB was comparable to that of normal subjects and patients with RA \[[@B23]\].

In addition, unlike murine CD25^high^ Treg cells, those isolated from humans include different cell subsets that, although developmentally related, display different phenotype and function. On this basis, in 2011, Miyara and Sakaguchi suggested that the assessment of CD45RA on the cell surface and of Helios transcription factor may help to distinguish Treg cell subsets with consistent suppressive activity. Unfortunately such approach was not employed in the majority of studies investigating Treg cell in pSS; hence several issues concerning the reproducibility and comparability of different studies remain open \[[@B31]\].

Finally, it has been recently put forward the hypothesis that CD25 expression is not mandatory to confer a regulatory phenotype \[[@B32]\]. In this setting, recent studies identified a T lymphocyte subpopulation expressing FoxP3, but lacking CD25 surface molecule, that is expanded in the PB of patients with SLE \[[@B33], [@B34]\]. However, the lack of a consistent suppressive activity exerted by CD25^−^FoxP3^+^ cells underscored the need to identify more specific Treg cell markers to be combined with FoxP3. Translating the knowledge on murine Treg cells to humans, the glucocorticoid induced tumor necrosis factor receptor related protein (GITR), a well-characterized marker of Treg cells in mice, gained growing scientific interest \[[@B35]\]. In fact, GITR and FoxP3 coexpression allows identifying T cells with regulatory phenotype and function independently of CD25 expression in normal subjects. Of interest, GITR blockade abrogates their suppressive activity suggesting that this molecule is involved in conferring regulatory properties \[[@B36]\].

Moreover, a functionally suppressive CD25^low/−^GITR^+^ cell subset was found to be expanded in the PB of patients with SLE or pSS and this expansion was associated with a reduction of conventional CD25^high^ Treg cells \[[@B26], [@B37]\]. Intriguingly, the expansion of CD25^low/−^GITR^+^ cell was more pronounced in patients with inactive disease suggesting a certain attempt to rebalance the reduction of conventional Treg cells that is working, at least, in milder disease.

Moving to tissue level, the evaluation of Treg cells in pSS minor salivary glands (MSGs) was performed in four studies \[[@B18], [@B21], [@B23], [@B26]\]. Li et al. observed a reduced number of CD25^+^ cells in pSS-MSGs compared to those with nonautoimmune parotitis \[[@B18]\]. However, taken the fact that also activated cells may express CD25, these observations do not allow drawing any definitive conclusion on the presence of Treg in pSS-MSGs. Therefore, FoxP3 has been subsequently analyzed with either immunohistochemistry \[[@B18], [@B21], [@B23], [@B26]\] or polymerase chain reaction \[[@B18]\], showing a consistent expression of this transcription factor and supporting the presence of Treg cells in pSS-MSG mononuclear cell infiltrate. Of note, however, both CD25^+^ and CD25^−^ cells were included in the FoxP3^+^ area within the salivary gland infiltrate, and some of them coexpressed GITR, suggesting the presence of not only conventional CD25^high^, but also the aforementioned CD25^low/−^GITR^+^ suppressive cell subset in MSG during pSS \[[@B26]\].

Of particular interest, an attempt to correlate FoxP3 staining, namely the amount of infiltrating Treg cells, and the extent of glandular involvement was also pursued in two studies \[[@B21], [@B23]\]. A direct correlation between FoxP3 staining and either Sarigul et al. \[[@B23]\] focus score or Tarpley\'s score \[[@B21]\] was observed. These findings, concerning the correlation between the amount of infiltrating Treg cells and the severity of tissue inflammation, are in line with those obtained in rheumatoid synovium and point out the role of Treg cells in counteracting local tissue inflammation that, however, may be ineffective \[[@B38], [@B39]\].

In fact, although the*in vitro* functional assays performed in four studies pointed out that the suppressive activity of PB CD25^high^ cells seems preserved in pSS \[[@B17], [@B18], [@B22], [@B26]\], it is not possible to ascertain whether Treg cells are able to exert their suppressive activity*in vivo* or they are affected by local inflammatory microenvironment.

3. IL-17-Producing T Cells in pSS {#sec3}
=================================

IL-17 is a family of cytokines including six members, from A to F, with a wide range of biological activities \[[@B40]\]. Besides physiological processes, such as host defense against microbial infections, IL-17 is a leading actor in pathologic conditions, including cancer and autoimmune disorders, due to a strong proinflammatory potential \[[@B41]\]. In fact, upon binding to its receptor, IL-17 triggers downstream events culminating in the transcription of proinflammatory genes, such as cytokines, chemokines, and matrix degrading enzymes, by target cells \[[@B10]\]. Although the main cellular source of IL-17 is represented by T lymphocytes, growing evidence suggests that also neutrophils and mast cells participate in the balance of this cytokine \[[@B42], [@B43]\].

The commitment of a naïve CD4^+^T lymphocyte towards a T helper (Th) 17 cell occurs in the presence of a peculiar cytokine milieu. Indeed, the upregulation of the retinoic acid orphan receptor (ROR) *γ*t transcription, the expression of IL-17, and the stabilization of the Th17 phenotype require the concurrent presence of IL-6, TGF-*β*, IL-21, IL-1*β*, and IL-23. Besides IL-17, Th17 cells are able to produce also IL-21 and IL-22. IL-21 collaborates with dendritic cell-derived TGF-*β* to amplify the tendency to Th17-cell differentiation and induces these lymphocytes to express receptors for IL-23. The latter cytokine is required for the maintenance of Th17 phenotype \[[@B15]\].

In addition, it has been recently reported that a subset of Th17 cells, as identified by the coexpression of CCR6 and CXCR3, is able to produce also IFN-*γ* \[[@B44]\]. Taken the well-established role of IFN-*γ* in the pathogenesis of autoimmune diseases, including pSS, this intriguing finding further underscores the relevance of Th17 cells in such scenario.

It is interesting that, at least in mice, Th17 lymphocytes can also function as B-cell helpers \[[@B45]\]. They induce, indeed, a pronounced antibody response, with preferential immunoglobulin (Ig) class switch to IgG2a and IgG3 for IL-17 and to IgG1 and IgG2b for IL-21. These results establish that Th17 cells are crucial in germinal center (GC) formation. As suggested above, the proinflammatory IL-17, normally considered a T-cell-associated factor, has been also reported to be a central driver of GC-derived autoantibodies. This was demonstrated by blocking IL-17 signaling that disrupted the CD4^+^T-cell and B-cell interactions required for GC formation \[[@B46]\].

The evidence that IL-17-knockout (KO) mice are less prone to develop autoimmune diseases such as type 1 diabetes, collagen-induced arthritis, and experimental autoimmune encephalomyelitis \[[@B41], [@B47]\] raised the hypothesis that this cytokine, and therefore IL-17-producing cells, may also be involved in the pathogenesis of pSS. Experimental SS in the IL-17-KO mouse was only recently evaluated \[[@B48]\]. Despite being immunized with salivary gland peptides, these animals did not develop any histological signs of salivary gland inflammation. Intriguingly, the adoptive transfer of Th17 cells was able to induce a focal sialadenitis similar to that of wild type mice, underscoring the pathogenic role of IL-17 also in pSS. It is of note, that already in 2008, Nguyen et al. first reported that IL-17 overexpression in salivary glands by adenovirus vectors was able to trigger a SS-like condition in nonsusceptible mice \[[@B49]\]. In this setting, three studies described that IL-17 is consistently expressed in the periductal infiltrates of all MSGs from patients with pSS \[[@B50]--[@B52]\] and in two of them such expression was found to be associated with the severity of glandular inflammation \[[@B51], [@B52]\].

In addition, most of the cytokines that support the Th17 phenotype as well as other Th17-cell products, including IL-6, IL-21, IL-22, and IL-23 and their receptors, are consistently expressed in MSGs of patients with pSS \[[@B50], [@B52]--[@B57]\]. Similar to IL-17, also IL-21 expression in MSGs appears to parallel the severity of glandular inflammation \[[@B53]\].

The main cellular source of glandular IL-17 in pSS-MSGs appears to be constituted by CD4^+^ and, to a lesser extent, CD8^+^ T lymphocytes \[[@B58], [@B59]\]. Of interest, however, two recent studies pointed out that also CD4^−^CD8^−^ (double negative, DN) T cells \[[@B60], [@B61]\] and mast cells \[[@B55]\] may participate in IL-17 local balance in pSS.

DN T cells were initially identified as a source of IL-17 in SLE \[[@B62]\] and their presence in the inflammatory infiltrate of kidney during lupus nephritis suggested a pathogenic role of this cell subset in SLE. In pSS, DN T cells were found to be associated not only with the extent of glandular involvement, as already demonstrated for IL-17 \[[@B51], [@B52]\], but also with the presence of MSG ectopic lymphoid structures, which have been associated with more severe clinical phenotype, including B-cell lymphoma \[[@B7], [@B63]\]. This evidence appears to support the pathogenic role of IL-17 and IL-17-producing cells not only in the induction but also in the perpetuation of glandular lesions.

IL-17 and its related cytokines have also been evaluated in other biological samples from pSS patients such as saliva, tears, and serum. To date, only one study assessed IL-17 in pSS saliva reporting higher levels of this cytokine compared to non-pSS, but failing to identify any association between the concentration of this cytokine and the extent of MSG lymphocytic infiltration \[[@B64]\].

In addition, there is general agreement among available studies of increased IL-17 concentration in the tears of pSS patients compared to non-pSS dry eye \[[@B65]--[@B68]\].

As far as serum is concerned, the four studies that assessed IL-17 pointed out that only a subgroup of pSS patients display detectable levels of this cytokine \[[@B50], [@B51], [@B69], [@B70]\], but only two of these found an association between serum IL-17 and clinical/histological features of pSS \[[@B69], [@B70]\]. In particular, it was shown that disease duration was significantly longer and parotid gland swelling was less prevalent in IL-17-positive patients compared to those IL-17-negative ones. However, multivariate analysis revealed that disease duration was associated with the presence of serum IL-17 independently of concurrent parotid gland swelling \[[@B70]\]. Furthermore, IL-17 serum concentration was higher in patients with ectopic GC-like structures compared to those without GCs \[[@B69]\].

Also IL-21 has been found to be increased in pSS serum \[[@B53]\], while IL-6 and IL-23 have been found to be increased in pSS plasma in association with increased levels of IL-17 \[[@B52]\].

To shed additional light on peripheral IL-17 balance, enumeration of IL-17-producing cells in the PB has been performed in a series of studies. An overall increase of circulating CD4^+^Th17 cells \[[@B51], [@B59]--[@B61]\] and DN T cells \[[@B60], [@B61]\] has been described in pSS patients compared to controls. Intriguingly, however, in a study performed by our group, differences in the percentage of these cell subsets according to disease duration were also highlighted. It appeared, indeed, that in early pSS, with symptom duration less than 18 months, CD4^+^Th17 cells were expanded, while DN T cells were comparable to those of normal subjects. Conversely, in patients with established disease and symptom duration over 5 years, CD4^+^Th17 cell percentage was comparable to that of controls and DN T cells were expanded \[[@B61]\].

Taken together, these findings in pSS MSG, serum/plasma, and PB suggest a highly dynamic scenario occurring in the course of the disease with a clear pathogenic role of IL-17 in triggering and maintaining glandular inflammation and a recirculation of IL-17-producing T-cell subsets from PB to MSG and vice versa in different phases of the disease ([Table 1](#tab1){ref-type="table"}). However, despite their clear pathogenic role, no association between IL-17/Th17 cells and severity of clinical picture or specific extraglandular clinical manifestations has been reported \[[@B71]\].

We believe that this last consideration does not diminish but rather reinforces the role of IL-17/Th17 system in pSS pathogenesis. In fact, this biological system is crucial in the induction as well as in the maintenance of pSS, independently of the clinical or serological features of the disease, thus representing an interesting and promising therapeutic targeting in this disease.

In conclusion, although interesting, all the aforementioned studies evaluating Treg and Th17 cells are weighted by a number of intrinsic limitations that deserve some consideration. First, pSS is a heterogeneous disease characterized by different genetic background (e.g., HLA haplotypes), clinical manifestations (glandular versus extraglandular), and serological status (anti-SSA, anti-SSB, both, or none). All the above imply different therapeutic approaches (lacrimal or salivary substitutes versus immune suppressants). Since in most studies patients are not subgrouped according to disease features, including disease duration or therapy, results may be biased. Furthermore, the majority of investigations are performed in peripheral blood rather than target organs providing a partial view on such scenario. Therefore, the balance of different cytokines and soluble mediators as well as their effects on T cells should be investigated*in vivo* rather than*in vitro*. Finally, it is still a matter of debate whether Treg cell impairment and Th17 cell predominance may be either a cause or a consequence of the ongoing inflammation.

4. Therapeutic Perspectives {#sec4}
===========================

pSS is an autoimmune disorder affecting exocrine glands and is characterized, in most cases, by a rather mild clinical picture. However, a subgroup of pSS patients experience systemic extraglandular involvement leading to a worsening of disease prognosis. Current therapeutic options for the treatment of pSS are mainly empiric, often translated by other autoimmune diseases, and recent systematic reviews highlighted the lack of evidence-based recommendations for most of the immunosuppressive drugs commonly employed in the spectrum of extraglandular involvement. In this setting, therefore, pSS may be still considered an orphan disease \[[@B72]--[@B75]\].

In recent years, the effects of currently available therapies on Treg and Th17 cells have been extensively investigated in autoimmune diseases, in particular RA and psoriasis \[[@B40], [@B76]\]. Unfortunately, however, very few data concerning this issue are available in pSS. This is partially explained by the fact that only a subgroup of patients display extraglandular manifestations requiring immunosuppressive therapies. Furthermore, most of the biologic therapies employed in RA are not currently used in pSS for the lack of either proven clinical efficacy (e.g., TNF blockers), clinical trials (e.g., tocilizumab), or, although effective, specific licensing (e.g., abatacept).

It is of note, however, that corticosteroids (CS) may affect the IL-17 axis during pSS. Although a case report described infiltrate reduction in one patient with pSS receiving CS at high doses, no further evidence supports the efficacy of CS in reducing glandular inflammation to date \[[@B77], [@B78]\]. Subsequently, it has been demonstrated that the subset of IL-17-producing DN T lymphocytes, isolated from pSS patients, is resistant to CS*in vitro* \[[@B60]\]. Conversely, DN T cells from normal controls promptly respond to CS*in vitro* by reducing IL-17 production. These observations give rise to an intriguing line of investigation in the clinical scenario of CS-resistance of autoimmune/inflammatory diseases.

As far as Treg cell selective therapeutic targeting is concerned, approaches promoting the*in vivo* expansion of Tregs or injection of*in vitro* expanded autologous/heterologous Tregs are under intense investigation in different acute and chronic diseases to date with promising results. In particular, data from murine studies suggest that the transfer of autologous Treg cells is able to prevent the development of collagen-induced arthritis and colitis, while*ex vivo* expanded CD4^+^CD25^+^ Treg cells can attenuate the development of experimental autoimmune encephalomyelitis and ameliorate type I diabetes \[[@B35]\]. In humans, Treg cells transfer is able to prolong immune tolerance following hematopoietic stem cell transplantation and to prevent graft-versus-host disease \[[@B80]\]. Treg cell transfer is safe in patients with severe Crohn\'s disease \[[@B81]\] and an open-label phase I trial to investigate safety and efficacy of intravenous infusion of*ex vivo* selected and expanded autologous polyclonal Treg cells in patients with type 1 diabetes is currently ongoing (trial [NCT01210664](https://clinicaltrials.gov/ct2/show/NCT01210664?term=NCT01210664&rank=1)). These encouraging results allow speculating that reprogramming Treg cells or infusing*in vitro* expanded autologous/heterologous Treg cells may affect the natural history of autoimmune diseases \[[@B82]\]. However, two main concerns limit the possible employment of Treg cell therapy. First, taken the aforementioned debate about the specificity of CD25 as Treg cell marker, additional molecules should be identified to isolate and expand the most suitable Treg cell subset. In this setting, since under some conditions, the regulatory activity of CD4^+^CD25^high^GITR^+^ cells is superior to that of CD4^+^CD25^high^GITR^−^ cells, GITR may be a good candidate \[[@B35]\].

Second, stability and fate of transferred Treg cells*in vivo* are not predictable and, according to recent findings, they may be converted into effector cells, namely, Th17 cells, by proinflammatory cytokines \[[@B16], [@B83]\].

On the other hand, the growing amount of data supporting the pathogenic role of IL-17 axis in the pathogenesis of pSS provided the rational for a number of clinical trials that are currently ongoing in pSS.

Two monoclonal antibodies against IL-17 (the fully human IgG1k secukinumab and the humanized IgG4 ixekizumab) are being investigated in inflammatory arthritides \[[@B84]\] and a clinical trial evaluating secukinumab in dry eye patients is currently ongoing (trial [NCT01250171](https://clinicaltrials.gov/ct2/show/NCT01250171?term=NCT01250171&rank=1)).

Concerning the molecules that are involved in the balance between Treg and Th17 cell commitment, the humanized anti-IL-6 antibody tocilizumab is employed in clinical practice for the treatment of RA and a phase II trial to assess its efficacy in pSS is currently ongoing (trial [NCT01782235](https://clinicaltrials.gov/ct2/show/NCT01782235?term=NCT01782235&rank=1)). Since IL-6 presence or absence in the local microenvironment drives the polarization of a naïve T cell to a Th17 or a Treg phenotype, respectively, it would be of great interest to ascertain the effect of IL-6 blockade in such a scenario.

Compounds targeting IL-23 and IL-21 have been or are under investigation in plaque psoriasis and chronic inflammatory arthritides, but not yet in pSS \[[@B85], [@B86]\].

Another interesting aspect is the possible effect on IL-17 axis exerted by non-T-cell selective compounds. In fact, previous studies that investigated the effects of anti-CD20 antibody rituximab on T lymphocytes in RA revealed that this compound is able to deplete CD4^+^Th17 cells in PB and synovium as they coexpress CD20 \[[@B87]--[@B89]\]. Taken that rituximab is currently the most employed biologic agent in pSS \[[@B90]\], if these observations will be confirmed in the PB and MSG of pSS patients, an additional rational for therapeutic application of rituximab in pSS may be defined.

Finally, another intriguing approach is represented by the interference with Th17 commitment via the modulation of ROR*γ*t activity in the thymus. A study that employed a synthetic ligand binding to this transcription factor in a mouse model of multiple sclerosis reported impressive clinical efficacy \[[@B91]\].

These data point out the need of randomized clinical trials to investigate the safety and efficacy of these drugs in pSS in order to provide solid scientific evidence. Taken together, the difficulty to build therapeutic recommendations in pSS may be related to the heterogeneity of clinical picture, the frequent failure of first line treatments, the lack of scientific evidence for drugs licensed for other diseases, and, finally, the lack of innovative therapeutic compounds.

5. Conclusion {#sec5}
=============

pSS encompasses several subsets of patients with different genetic background, pathophysiological pathways, demographic features, and different response to proposed therapies. Despite the acknowledged role of T-cell subsets in pSS, mechanisms leading to their abnormal activation and their contribution to pSS pathogenesis are not fully elucidated. In particular, only few studies evaluated the role of Treg cells in pSS, and conclusive data are still lacking. Similarly, although conventional CD4^+^Th17 and IL-17-producing DN T cells are under active investigation, their origin, fate, and function are still a matter of debate. Currently available data suggest a pivotal role of IL-17 axis and IL-17-producing cells in every step of pSS pathogenesis, from the induction of autoimmune epithelitis to the maintenance and perpetuation of inflammation and ectopic GC formation. In this context, IL-17-producing T cells seem to be a link between T- and B-cell compartments. In this setting, a therapeutic approach targeting IL-17 axis may represent an intriguing issue worth to be investigated in pSS. In the era of biologic agents, randomized double-blind controlled trials represent the most powerful tool to obtain comparable results and provide the rationale to build solid therapeutic recommendations also in pSS.

Conflict of Interests
=====================

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors\' Contribution
======================

Alessia Alunno and Francesco Carubbi contributed equally to this review article.

![Cellular and molecular players in the pathogenesis of primary Sjögren\'s syndrome. MHC = major histocompatibility complex, TLR = toll-like receptor, DC = dendritic cell, Th = T helper cell, IFN = interferon, IL = interleukin, APC = antigen presenting cell, Treg = T regulatory cell, PC = plasma cell, GC = germinal center, TGF = transforming growth factor.](MI2015-243723.001){#fig1}

######

Indicators of Treg cell and IL-17/IL-17-producing T cell involvement in primary Sjögren\'s syndrome.

  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
  Source                         Observation                                                                                References
  ------------------------------ --------------------------------------------------------------------------------------------------------------------------- --------------------------------------
  Salivary glands                FoxP3 expression is associated with the severity of glandular inflammation  \                                               \[[@B21], [@B23]\] \
                                 Inverse relationship between glandular and circulating FoxP3+ cells  \                                                      \[[@B21]\] \
                                 Lower FoxP3+ cells correlate with adverse predictors for lymphoma development  \                                            \[[@B21]\] \
                                 CD25low/-GITR+ T cells are present in mononuclear cell infiltrate \                                                         \[[@B26]\] \
                                 High expression of IL-17 and IL-17R \                                                                                \[[@B50]--[@B52]\] \
                                 High expression of IL-6, IL-21, IL-22, and IL-23 \                                                                          \[[@B50], [@B52]--[@B57]\] \
                                 CD4+, CD8+, mast cells, and DN T cells produce IL-17 \                                                                      \[[@B55], [@B60], [@B61]\] \
                                 IL-17 is associated with the severity of glandular damage \                                                                 \[[@B51], [@B52]\] \
                                 DN T cells are associated with GCs                                                                                \[[@B61]\]

  Saliva/tears                   Increased levels of IL-17 in saliva \                                                                                \[[@B64]\] \
                                 Increased levels of IL-17 in tears \                                                                                \[[@B65]--[@B67]\] \
                                 No association between salivary IL-17 and glandular damage                                                                  \[[@B64]\]

  Serum                          Increased levels of IL-17 \                                                                                \[[@B50], [@B51], [@B69], [@B70]\] \
                                 Increased levels of IL-6, IL-21, and IL-23 \                                                                                \[[@B52], [@B53]\] \
                                 IL-17 prevalence is dependent on disease duration \                                                                         \[[@B70]\] \
                                 Serum IL-17 is higher in patients with MSG-GCs                                                                              \[[@B69]\]

  Peripheral blood               Altered Treg cell percentage (increased, decreased, or comparable percentages with\                                         \[[@B17]--[@B26]\] \
                                 respect to HD) \                                                                                \[[@B19]\] \
                                 Inverse correlation between the percentage of Treg cells and CRP, ESR, RF, and IgG \                                        \[[@B25], [@B26]\] \
                                 No differences in Treg cell percentage according to ESSDAI and SSDAI \                                                      \[[@B26]\] \
                                 Expansion of functionally suppressive CD25low/-GITR+T cells \                                                               \[[@B26]\] \
                                 Suppressive CD25low/-GITR+T cell percentage are expanded in inactive pSS \                                                  \[[@B26]\] \
                                 Increase of circulating CD4+Th17 cells \                                                                                \[[@B51], [@B59]--[@B61]\] \
                                 Increase of circulating IL-17+DN T cells                                                                                \[[@B60], [@B61]\]

  Intrinsic cell abnormalities   The Vbeta repertoire of pSS Treg cells is polyclonal and not significantly restricted as compared with that in controls \   \[[@B17]\] \
                                 IL-17-producing DN T cells are totally insensitive to dexamethasone *in vitro* \                                             \
                                 IL-17A gene displays an association with GC status                                                                          \[[@B60]\] \
                                                                                \[[@B92]\]
  -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Treg = T regulatory cells; IL = interleukin; Th17 = IL-17-producing T helper cells; FoxP3 = Forkhead box protein P3; GITR = glucocorticoid-induced tumor necrosis factor receptor related protein; DN = IL-17-producing double negative T cells; GC = germinal center; CRP = C reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor; IgG = immunoglobulin G; ESSDAI = EULAR Sjögren\'s syndrome disease activity index; SSDAI = Sjögren\'s syndrome disease activity index; and HD = healthy donors.

[^1]: Academic Editor: Alex Kleinjan


local awful = require('awful')
local gears = require('gears')
local beautiful = require('beautiful')

-- Signal function to execute when a new client appears.
client.connect_signal(
	'manage',
	function(c)
		-- Focus, raise and activate
		c:emit_signal(
			'request::activate',
			'mouse_enter',
			{
				raise = true
			}
		)

		-- Set the windows at the slave,
		-- i.e. put it at the end of others instead of setting it master.
		if not awesome.startup then
			awful.client.setslave(c)
		end

		if awesome.startup and not c.size_hints.user_position and
			not c.size_hints.program_position then

			-- Prevent clients from being unreachable after screen count changes.
			awful.placement.no_offscreen(c)
		end

		-- Spawn client with rounded corners (of course it will follow the theme.client_radius)
		-- if client's first_tag is not maximized and round_corners = false
		local current_layout = awful.tag.getproperty(c.first_tag, 'layout')
		if not c.round_corners or (current_layout == awful.layout.suit.max and not c.floating) then return end
		c.shape = function(cr, width, height)
			gears.shape.rounded_rect(cr, width, height, beautiful.client_radius or 6)
		end
	end
)

-- Enable sloppy focus, so that focus follows mouse then raises it.
client.connect_signal(
	'mouse::enter',
	function(c)
		c:emit_signal(
			'request::activate',
			'mouse_enter',
			{
				raise = true
			}
		)
	end
)

client.connect_signal(
	'focus',
	function(c)
		c.border_color = beautiful.border_focus
	end
)

client.connect_signal(
	'unfocus',
	function(c)
		c.border_color = beautiful.border_normal
	end
)

-- Manipulate client shape on fullscreen/non-fullscreen
client.connect_signal(
	'property::fullscreen',
	function(c)
		if c.fullscreen then
			c.shape = function(cr, width, height)
				gears.shape.rectangle(cr, width, height)
			end
		else
			local current_layout = awful.tag.getproperty(c.first_tag, 'layout')
			if (current_layout == awful.layout.suit.max) and (not c.floating or not c.round_corners or c.maximized) then
				c.shape = function(cr, width, height)
					gears.shape.rectangle(cr, width, height)
				end
			else
				c.shape = function(cr, width, height)
					gears.shape.rounded_rect(cr, width, height, beautiful.client_radius or 6)
				end
			end
		end
	end
)

-- Manipulate client shape on maximized
client.connect_signal(
	'property::maximized',
	function(c)
		local current_layout = awful.tag.getproperty(c.first_tag, 'layout')
		if c.maximized then
			c.shape = function(cr, width, height)
				gears.shape.rectangle(cr, width, height)
			end
		else
			if (current_layout == awful.layout.suit.max) and
				(not c.floating or not c.round_corners or c.maximized) then return end
			c.shape = function(cr, width, height)
				gears.shape.rounded_rect(cr, width, height, beautiful.client_radius or 6)
			end
		end
	end
)

-- Manipulate client shape on floating
client.connect_signal(
	'property::floating',
	function(c)
		local current_layout = awful.tag.getproperty(c.first_tag, 'layout')
		if c.floating and not c.maximized then
			c.shape = function(cr, width, height)
				gears.shape.rounded_rect(cr, width, height, beautiful.client_radius or 6)
			end
		else
			if current_layout == awful.layout.suit.max then
				c.shape = function(cr, width, height)
					gears.shape.rectangle(cr, width, height)
				end
			end
		end
	end
)


k(b) = 2*b + 14. Let i(x) = x + 6. Let u(j) = 7*i(j) - 3*k(j). Let h(w) = 4*w - 9. Let z(m) = -2*h(m) + 6*u(m). Let c(n) = n. What is c(z(f))?
-2*f + 18
Let j(q) = 13*q. Let g(s) = -21*s + 0 + 0*s + 0 + 15*s. Determine g(j(b)).
-78*b
Let t(l) = -l**2 + 3*l. Let o(v) = v**2 - 7*v. Let u(b) = -6*o(b) - 14*t(b). Let m(h) = -6*h. Determine u(m(d)).
288*d**2
Let l(g) = 20*g**2. Suppose 107 = -2*x + 111. Let b(h) = 4*h + 2*h**x - 7*h + 3*h. Calculate l(b(t)).
80*t**4
Let r(v) = 5*v - v + v - 4*v + 0*v. Let s(p) = 50*p**2. Calculate s(r(k)).
50*k**2
Let d(r) = 2*r**2. Let c(k) = k. Let x(b) = -3*b + 12. Let n(i) = 2*c(i) + x(i). Calculate n(d(u)).
-2*u**2 + 12
Suppose 0 = 45*x - 46*x + 16. Let o(h) = x*h - 4*h - h + 4*h. Let d(c) = -c. Give o(d(t)).
-15*t
Let f(o) be the third derivative of 0 + 0*o**4 + 0*o**3 + 1/10*o**5 - 2*o**2 + 0*o. Let i(m) be the first derivative of -m**2 - 1. Calculate i(f(z)).
-12*z**2
Let j(u) = u. Let s(o) = -o - 3. Let k(m) = -m**2 - 5*m - 4. Let p be k(-5). Let c(h) = 9 + 1 - 10 + 0 - 4. Let w(i) = p*s(i) + 3*c(i). Calculate j(w(q)).
4*q
Let v(r) = 4*r. Let p(q) = 3 + 34*q + 2*q**2 + 10 - 13. Calculate p(v(c)).
32*c**2 + 136*c
Let n(z) = 72*z**2. Let c(f) be the third derivative of -f**5/20 - 2*f**2 - 30. Determine c(n(b)).
-15552*b**4
Let j(w) = -5*w. Let f(n) be the first derivative of 0*n**4 + 0*n - 4 + 3*n**2 + 0*n**3 + 1/30*n**5. Let p(c) be the second derivative of f(c). What is p(j(g))?
50*g**2
Let g(w) = 5*w. Let y(z) = -16*z**2 + 5068*z. Determine y(g(p)).
-400*p**2 + 25340*p
Let b(z) = 4*z**2. Let d(s) be the second derivative of -7*s**4/12 + s**2/2 + 192*s. Give d(b(t)).
-112*t**4 + 1
Let y(q) = 13*q + 13. Let j(l) = -3*l - 3. Let t(d) = -9*j(d) - 2*y(d). Let n(p) = 4. Let z(i) = n(i) - 4*t(i). Let v(k) = -7*k**2. Give z(v(r)).
28*r**2
Let b(u) = u - 1. Let m(o) = -5*o**2 + 3*o - 3. Let a(d) = 3*b(d) - m(d). Let p(n) = 32*n + n**2 + 22*n + 21*n - 75*n. Calculate a(p(x)).
5*x**4
Let m(o) = -15*o. Let d(h) = -24515*h. Calculate m(d(r)).
367725*r
Let z be 6/2*12 - -3. Let j(d) = z - 39 + 4*d + d. Let u(t) = 5*t - 3. Let m(i) = -44*i + 26. Let x(g) = 6*m(g) + 52*u(g). Determine x(j(v)).
-20*v
Let y(q) = q**2. Let n(u) be the second derivative of 0*u**3 - 1/4*u**4 + 10*u + 0 + 0*u**2. Give y(n(g)).
9*g**4
Let n(a) = 18*a**2 + 13*a - 13. Let p(r) = 4*r**2 + 3*r - 3. Let b(t) = 6*n(t) - 26*p(t). Let d(c) = 10*c**2. What is d(b(l))?
160*l**4
Let p(z) = -4543*z. Let o(y) = 64*y. Suppose 0 = 27*d - 30*d + 1062. Let h(r) = d*o(r) + 5*p(r). Let t(x) = -x**2. What is h(t(n))?
59*n**2
Let r(g) = -3*g. Let j(h) = -1423*h**2. Determine r(j(b)).
4269*b**2
Let n(z) be the third derivative of -z**5/20 - 24*z**2. Let g(r) = -12*r**2. Calculate n(g(j)).
-432*j**4
Let w(v) = 4*v**2. Let r(q) be the second derivative of 0 + 0*q**3 + 0*q**2 - 26*q + 5/12*q**4. Determine w(r(a)).
100*a**4
Let u(d) = -2*d. Let t(a) = -13*a - 23. Let i(s) = 32*s + 46. Let o(l) = -3*i(l) - 7*t(l). Give o(u(n)).
10*n + 23
Let v(c) = -c. Let a(m) = -111*m**2 + 33*m. Let g(f) = -14*f**2 + 4*f. Let y be ((-4)/(-3))/(-5 + (-96)/(-18)). Let p(h) = y*a(h) - 33*g(h). Determine p(v(s)).
18*s**2
Let u(s) = -s. Let f(r) = 4625*r**2 + 50. Determine u(f(j)).
-4625*j**2 - 50
Let d(v) = 8*v**2. Let k(l) = -5*l + 18. Let a(h) = 16*h - 51. Let w(i) = -6*a(i) - 17*k(i). Give w(d(m)).
-88*m**2
Let m(i) = -10*i - 3. Let t(x) = -715*x. Calculate t(m(a)).
7150*a + 2145
Let z be (-28)/(-20) + -1 - 1/15. Let x(y) be the first derivative of 0*y + z*y**3 + 7 + 0*y**2. Let g(o) = o. Determine g(x(b)).
b**2
Let x(o) = 4870*o. Let z(d) = 24*d**2 - 2. Calculate x(z(t)).
116880*t**2 - 9740
Let a(f) = -2*f. Let h(x) = x**2 - 7*x - 8. Let m be h(8). Suppose m*p - p = -2. Let l(j) = 203*j + 7*j**p - 203*j. Give a(l(n)).
-14*n**2
Let l(p) = -13*p**2 + 5*p**2 - p**2. Let d(s) be the first derivative of s**5/60 - 3*s**2 - 2. Let m(b) be the second derivative of d(b). Calculate m(l(f)).
81*f**4
Let g be (-64)/6 - (57 - 68). Let n(r) be the first derivative of 4 + g*r**3 + 0*r + 0*r**2. Let p(h) = 3*h**2. Calculate p(n(k)).
3*k**4
Let q(u) = -2584*u. Let i(x) = -16*x**2. What is i(q(w))?
-106832896*w**2
Let s(g) = 2. Let r(d) = -d**2 + 1. Let y(c) = 2*r(c) - s(c). Suppose -12 = o - 5*o - 2*a, 4*o - 4*a = 0. Let v(j) = -3*j**2 - 2*j**o + 2*j**2. Give v(y(q)).
-12*q**4
Let y(d) = 5*d**2. Suppose -2*m = -2*u, 4*u - 12 - 4 = -4*m. Let v(r) = -r**2 - 5*r**2 + 2*r**u + 3*r**2. What is v(y(x))?
-25*x**4
Let i(t) = 4*t**2. Let z(n) = -36*n**2. Let d(v) = -52*i(v) - 6*z(v). Let f(w) = 29*w**2. Determine f(d(x)).
1856*x**4
Let n(u) = -3*u. Let q(t) be the second derivative of t**3/6 - 29*t**2/2 + 161*t. What is n(q(y))?
-3*y + 87
Let z(f) = -44 + 4*f**2 + 44. Let k(h) be the third derivative of 0 + 0*h + 4*h**2 + 0*h**3 + 1/8*h**4. What is z(k(v))?
36*v**2
Let w(m) = 2*m. Let f(z) = -1662*z**2. What is w(f(l))?
-3324*l**2
Let s(c) = 6*c - 3*c + 2 - 1 + 2 - 5*c. Let i(h) = 9*h. What is i(s(w))?
-18*w + 27
Let p(b) = -2*b. Let y(i) be the second derivative of -5*i**6/72 + 23*i**4/12 + 16*i. Let u(x) be the third derivative of y(x). What is p(u(d))?
100*d
Let d(s) = -697*s. Let y(m) = 19*m**2. Give d(y(r)).
-13243*r**2
Let s(c) = 9*c**2. Let p(h) = -51636*h. Calculate s(p(k)).
23996488464*k**2
Let h(m) be the second derivative of 67*m**3/3 - m**2/2 + 7*m - 4. Let o(u) = u**2. Calculate h(o(r)).
134*r**2 - 1
Let m(r) = -3*r**2 + 25*r - 2. Let i be m(8). Let x(n) = -9*n + i*n + 5 - 5. Let u(y) = -11*y**2. Give x(u(d)).
33*d**2
Let t(o) be the first derivative of 1/2*o**2 + 0*o + 7. Let c(p) = -2*p**2 - 2*p**2 + 10 - 10. Calculate c(t(b)).
-4*b**2
Let l(p) = -1. Let x(c) = 4*c + 2. Let z(g) = -2*l(g) - x(g). Let f(t) be the third derivative of -t**5/60 - 152*t**2. Give z(f(y)).
4*y**2
Let r(a) = 3*a. Let q = -3 - -26. Let u(f) = -20*f + 43*f - 10*f**2 - q*f. Calculate r(u(v)).
-30*v**2
Let v(p) = -52*p + 103*p - 47*p. Let q(y) = 2*y**2 - 68*y. Give v(q(z)).
8*z**2 - 272*z
Let z(s) = 15565*s - 35. Let k(o) = -o**2. What is z(k(p))?
-15565*p**2 - 35
Let l(j) be the third derivative of j**6/144 - j**4/8 + 6*j**2. Let b(i) be the second derivative of l(i). Let d(h) = -2*h**2. Give d(b(o)).
-50*o**2
Let b(f) = 16*f**2. Let p(g) = 28*g**2 + 22*g**2 - 82*g**2 + 25*g**2. What is p(b(z))?
-1792*z**4
Let x(m) = m + 904. Let v(u) = u + 58. What is x(v(t))?
t + 962
Let j(f) = 220*f**2 + 127*f**2 + 138*f**2 + 379*f**2 - 220*f**2. Let t(x) = 2*x**2. Determine j(t(w)).
2576*w**4
Let b(t) = 61*t**2 + 6*t. Let g(y) = -4698*y**2 - 464*y. Let k(c) = -232*b(c) - 3*g(c). Let r(x) = -8*x**2. Calculate r(k(j)).
-26912*j**4
Let p(v) be the third derivative of -v**5/20 + v**2. Let m(h) = -2*h. Let i(t) = -7*t. Let g(c) = 2*i(c) - 6*m(c). What is g(p(a))?
6*a**2
Let q(k) = 108492*k**2. Let j(f) = -f**2. Determine j(q(b)).
-11770514064*b**4
Let o(s) = -3*s. Let v(i) = 241270*i. Determine v(o(f)).
-723810*f
Let h(q) = 33*q + 3 - 65*q + 26*q - 3. Let b(p) = 4*p**2. Calculate b(h(j)).
144*j**2
Let a(x) = 22*x. Let j(v) = v - 7. Let u be j(-6). Let r = -11 - u. Let o(w) = 2*w**r - 3*w**2 - w**2. What is o(a(n))?
-968*n**2
Let c(d) = -10*d**2. Let q(w) = w - 159*w**2 + 136*w**2 - w. Determine c(q(j)).
-5290*j**4
Let c(p) = 21*p + 5. Let f(r) = -32*r - 7. Let h(s) = 7*c(s) + 5*f(s). Let b(j) = -j. Determine b(h(v)).
13*v
Let o(y) = -9*y**2. Let n(m) = -6*m - 16. Let a be n(-3). Let k(q) = 15*q**2 - q**2 - 12*q**a. Give o(k(l)).
-36*l**4
Let s(p) = 461809*p**2. Let h(u) = -3*u**2. Calculate s(h(q)).
4156281*q**4
Let a(d) = 5*d - 5*d + 12*d. Let n(r) be the first derivative of 3*r**2/2 + 16. Determine n(a(y)).
36*y
Let a(k) = 5*k. Let w(r) = 76*r - 1. Let l(i) = 27*i. Let f(y) = -8*l(y) + 3*w(y). Give a(f(v)).
60*v - 15
Let g(a) = -a**2. Let v be 15/(-2)*10/(-15). Let s(z) = 2 - 2 - 13*z + v*z. Give g(s(c)).
-64*c**2
Let c(g) = g. Let k(u) be the second derivative of -u**3/6 - 43*u. Let b(v) = 44*v. Let y(l) = b(l) + 55*k(l). What is y(c(w))?
-11*w
Let k(c) = 132*c. Let o(l) = 27557*l. Give k(o(i)).
3637524*i
Let x(g) = 0*g + 5*g + 16*g. Let c(b) = 7 - 11 + 2*b + 4. Calculate c(x(m)).
42*m
Let a(n) = 9*n**2. Let t(z) = 14*z**2 - 3*z - 129. Give t(a(r)).
1134*r**4 - 27*r**2 - 129
Let t = 8 - 7. Let u(a) = 2*a**2 + 5. Let n(g) = g**2 - 1.


Transcatheter Aortic Valve Replacement: The New Standard in Patients With Previous Coronary Bypass Grafting?
The aim of this study was to assess how the introduction of transcatheter aortic valve replacement (TAVR) has changed clinical practice and outcome in patients who have previously undergone coronary artery bypass grafting (CABG). A significant proportion of patients admitted for aortic valve replacement have previously undergone CABG and are therefore at increased operative risk in case of redo surgery. In-hospital outcome data were analyzed from patients with or without previous CABG undergoing isolated surgical aortic valve replacement or TAVR in Germany from 2007 to 2013. In total, 32,581 TAVR and 55,992 surgical aortic valve replacement procedures were performed in patients with (n = 6,221) or without (n = 82,352) previous CABG. TAVR increased markedly in patients with previous CABG, from 18 procedures in 2007 to 1,191 in 2013, while surgical aortic valve replacement decreased in these patients from 471 to 179 procedures. In 2013, TAVR was the preferred therapy in almost 90% of patients with previous CABG. In-hospital mortality was increased in patients with previous CABG compared with those without (7.6% vs. 6.3% for TAVR and 7.2% vs. 2.6% for surgical aortic valve replacement). Bleeding and stroke rates were also increased with redo surgical aortic valve replacement procedures (with vs. without previous CABG: stroke, 3.2% vs. 1.8%; relevant bleeding, 29.6% vs. 13.4%; acute kidney injury, 4.2% vs. 2.9%), whereas this was not the case with TAVR (stroke, 2.1% vs. 2.6%; relevant bleeding, 7.3% vs. 8.3%; acute kidney injury, 6.3% vs. 5.4% respectively). A similar influence was seen in resource utilization (discharge destination home: TAVR after CABG, 51%; surgical aortic valve replacement after CABG, 31%). Since its introduction in 2007, TAVR has been increasingly used in Germany in patients with previous CABG, and in-hospital outcome data support the trend away from redo surgery.


DateCoin is a dating service that uses neural networks and artificial intelligent algorithms based on working business model with blockchain use. DateCoin is the highly liquid utility token based on ERC20 standard with price rise mechanics implemented, secured by the growing active audience worldwide. The token is designed for the new international dating service, next generation of a successful product Denim. It features reliable growth mechanics based on a global expansion strategy.

Project Purposes

DateCoin's purpose is to create the world’s first intelligent dating service for quick and easy search and fruitful dating with perfectly matching partners.

The founders aim to employ cutting-edge technologies for intelligent dating with your soulmate or at least with the person who shares similar interests.

They are aiming to provide the following services,
1. Fast intelligent matching, based on face recognition technology.
2. Secure data storage, privacy and end-to-end encryption in chats.
3. A high efficiency of dating.
4. Automated intellectual verification and blockchain technology.

The goal of the project is to change fundamentally the sphere of dating sites in general. The launching to the ICO and a selling of the tokens DateCoin (DTC) will allow the company to develop the project efficiently, to finance its development and to promote the product to the international market.

The holders of the highly liquid tokens DTC will be provided with privileged conditions of use of the service, and with the possibility of a buy-back.

Their project audience includes several tens of thousands of active and beautiful girls interested in building relationships of convenience with successful men around the globe. They will readily accompany their partners for both trips for two and business trips.

With Crowdsale, They aim to significantly accelerate product development process. They will use Blockchain and intelligent algorithms to enhance cyber security, increase efficiency and solve the key problems of other dating
services.

The purpose of the project with examples

DateCoin is secured with working business model and growing audience of MVP, dating service Denim.

With the ability to encrypt correspondence users can be assured of the privacy and security of data storage.

They use blockchain to tackle the core problem of dating industry, user identification, and verification. No more fake accounts and bots.

The project DateCoin will provide its users with a fast and high-quality selection of partners based on a face recognition technology, as well as on the morphological and semantic analysis of conversations.

Automated intellectual verification will provide the service with the presence of only real profiles of women with their real photos.

Within the project, only the required services will be expected to be paid– no hidden charges.

In-app Token Usage Mechanics

DTC tokens will be used for in-app discounted purchases. All the prices will be nominated in two currencies:
1. Fiat currency (EUR, USD, etc)
2. DTC Tokens.

Depending on the volume of funds raised, they plan three scenarios for project development. In the most intensive scenario, the audience of their application will reach 12 million users in 23 countries by 2020. The active expansion of the project around the world will require significant costs for marketing and product promotion.

This is an independent report generated by a Coinschedule partner company. Coinschedule has no influence over its content and the views expressed may not reflect the views of Coinschedule. This is not investment advice, you are encouraged to do your own research and reach your own independent conclusions.


Two distinct effects of 12S-hydroxyeicosatetraenoic acid on platelet aggregation by zooxanthellatoxin-A and ionomycin.
The marine toxin zooxanthellatoxin-A (ZT-A) and the Ca2+ ionophore ionomycin caused aggregation in rabbit platelets. While ZT-A-induced platelet aggregation was inhibited by indomethacin, ionomycin-induced aggregation was potentiated by the drug. In contrast, both ZT-A- and ionomycin-induced accumulations of thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2), were completely inhibited by indomethacin. 12S-Hydroxyeicosatetraenoic acid (12-HETE), which could be accumulated in the presence of indomethacin, inhibited ZT-A-induced aggregation, but it potentiated the ionomycin-induced one. These results suggest that the different effects of indomethacin may be attributed to the distinct effects of 12-HETE on ZT-A- and ionomycin-induced platelet aggregations.


Cisplatin plus gemcitabine for treatment of breast cancer patients with brain metastases; a preferential option for triple negative patients?
To assess the efficacy and tolerability of Cisplatin plus Gemcitabine combination in patients with brain metastases (BM) from breast cancer (BC). Eighteen BC patients with BM who were treated with Cisplatin plus Gemcitabine regimen between 2003-2011 were evaluated. A median of 6 cycles of this regimen were received, in fifteen patients (83.3%) as first-line chemotherapy, in 2 as second- line and in 1 as third-line after diagnosis of BM. Dose reduction was performed in 11 (61.1%) patients; major reasons were neutropenia and leukopenia. Grade III neutropenia and Grade II trombocytopenia rates were 33.3% and 16.7% respectively. Overall response rate (ORR; complete+partial response rate) was 33.4% (n=6) for the entire study population; triple negative patients achieved an 66.6% ORR while hormone receptor (HR) positive patients had 25% and HER2 positive patients 12.5%. Median progression-free survival was 5.6 months (2.4-8.8 months, 95%CI) and longer in patients with triple negative breast cancer (TNBC) (median 7.4 months, 95%CI, 2.4-12.3 months) than the patients with other subtypes (median 5 months for HER2 positive and 3.6 months for HR positive patients). Median PFS of the patients with TNBC who received this regimen as first-line was 9.2 months (5.2-13.2 months, 95%CI). Cisplatin plus Gemcitabine may be a treatment option for patients with BM from breast cancer. Longer PFS and higher response rates are results that support the usage of this regimen especially for the triple negative subtype. However, further prospective and randomized trials are clearly required to provide more exact information.


Q:

Ways to generalize C++ code with different similar types

Currently I have the following code:
static void markPoolsFree(const TNetgroupPools &group_info, TObjectID netiface) {
    for (size_t i = 0; i<group_info.public_pools.length();i ++ ) {
        SDK::revokeIPPoolFromNetworkInterface(group_info.public_pools[i],netiface);
    }

    for (size_t i =0 ; i<group_info.private_pool.length(); i++) {
        SDK::revokeIPPoolFromNetworkInterface(group_info.private_pool[i].pool_id,
                                              netiface);
    }
}

which has basically the same logic, but differents in types group_info.public_pools[i] and group_info.private_pool[i], that's why in second loop we have to add .pool_id member call. These types are different and don't have any relationships.
I want to rewrite this code to make it more general, for example something like this (sketch):
// template function
template <typename Container, typename PredArgs>
static void revokeIPPool(const Container &pool, TObjectID netiface,
                         bool (*pred)(PredArgs pool_id, PredArgs netiface_id))
{
     for (size_t i = 0; i < pool.length(); ++i) {
         if (pred(pool[i], netiface)) {
             SDK::revokeIPPoolFromNetworkInterface(pool[i], netiface);
         }

     }
}

// calling code
static void markPoolsFree(const TNetgroupPools &group_info, TObjectID netiface) {
    revokeIPPool(group_info.public_pools, netiface, SDK::isPredicateTrue);
    revokeIPPool(group_info.private_pool, netiface, SDK::isPredicateTrue);
}

But the problem is in different types for public_pools and private_pool.
Question:
Could you give all ways how is possible to generalize this code with examples? I need C++03 code, but C++11/C++14 is acceptable.
My thoughts:

Instead of SDK::revokeIPPoolFromNetworkInterface make wrapperIPPool with overloads for both types and call SDK::revokeIPPoolFromNetworkInterface internally.
Overload revokeIPPool for both types (but it's code duplication, no improvement against original code)
Partial function template specialization for revokeIPPool (is this possible?)
Full function template specialization for revokeIPPool
Wrap function revokeIPPool in class and make partial class template specialization.

Questions:

Wich of my thoughts are correct?
What's about advantages and shortcomings?
Which is more idiomatic for C++03 or C++11?
Is there other solutions?

A:

In C++03 I'd use template specialization on a traits class. (The main reason for going through a traits class, rather than using direct function specialisation, or overload is that you can perform partial template specialisation for classes, but not functions - and while its not needed here, it may be something that is useful later )
static void markPoolsFree(const TNetgroupPools &group_info, TObjectID netiface) {
    markPoolsFreeImpl(group_info.public_pools, netiface);
    markPoolsFreeImpl(group_info.private_pools, netiface);
}

template<typename T>
static void markPoolsFreeImpl(POOLS pools, TObjectID netiface) {
    for (size_t i = 0; i<pools.length();i ++ ) {
       PoolId poolid = PoolListTrait<POOLS>::get(pools,i);
       SDK::revokeIPPoolFromNetworkInterface(poolid,netiface);
    }
}

template<typename T> class PoolListTrait {};

template<> class PoolListTrait<PublicPoolList> {
  static PoolId get(PublicPoolList pools, int i) { return pools[i]; }
}

template<> class PoolListTrait<PrivatePoolList> {
  static PoolId get(PrivatePoolList pools, int i) { return pools[i].pool_id; }
}


Detection for cross-reactive proteins in filarial worm Setaria equina, MCF-7 human breast cancer, and Huh-7 hepatoma cells.
This study aimed to detect the cross-reactive proteins in filarial parasite adult worm Setaria equina and two different tumor cell lines (MCF-7 human breast cancer and Huh-7 hepatoma cells). This was performed using rabbit anti-S. equina extract (SeqE) or DEC (Diethylcarbamazine citrate) polyclonal IgG antibodies by indirect ELISA and western blotting. The results indicated cross-reactive bands at 70 and 75 kDa in all extracts by anti-DEC and SeqE antibodies, respectively. In addition, the expression of 70 kDa protein was only reduced in filarial worms and Huh-7 after in vitro DEC treatment compared to the control.


Advanced, metastatic RCC disease is uniformly resistant to radiation and chemotherapy and it represents one of the most receptive cancers to immunotherapy.[@R1] However, the clinical response is weakened, mostly due to tumor-induced immune suppression that represents a major obstacle for successful cancer immunotherapy. Multiple immunosuppressive mechanisms have been identified in RCC that propagate conditions interfering with the development and activation of an effective anti-tumor response.[@R2]^,^[@R3] Tumor microenvironment, which encompasses immune, stromal and vascular cells, exerts profound immunosuppressive and tolerogenic activity on antigen presenting as well as T effector cells by secretion of bioactive proteins and lipids. Together, these factors favor conditions that allow tumors to escape immune recognition and foster proliferative and metastatic potential of tumor cells.

Growing body of evidence suggests that cancer progression is facilitated by enhanced production of eicosanoids that promote cancer inflammation, immune suppression, angiogenesis and proliferation of malignant cells.[@R4]^,^[@R5] Eicosanoids are enzymatic products of arachidonic acid (AA) and can be formed by cyclooxygenase (COX), lipoxygenase (LOX) or cytochrome P-450 epoxygenase. Importantly, eicosanoids strongly contribute to the immunoregulatory mechanisms and may control inflammation through regulation of cytokine and chemokine production. Arachidonate products of cycloxygenase and lipoxygenase pathways can be secreted in substantial amounts by both epithelial cancer cells and tumor-infiltrating inflammatory cells including tumor-associated macrophages and myeloid-derived suppressor cells.[@R6]^,^[@R7] Numerous studies provided clinical and pharmacological evidence for involvement of COX2-PGE2 pathway in the pathogenesis of various cancers, including colon, lung, breast and bladder cancers. The other AA metabolizing enzymes (e.g., lipoxygenases) have drawn less attention for their potential roles in human tumor initiation and/or progression.

Lipoxygenases (LOXs) are iron-containing dioxygenases that catalyze formation of fatty acid hydroperoxides from polyunsaturated fatty acids.[@R8] The specific bioactivities of LOXs include hydroperoxidase, leukotriene synthase, lipoxin synthase and hepoxylin synthase activities. Four major types of mammalian LOXs were described: 5-LOX, 8-LOX, 12-LOX and 15-LOX. In humans, two distinct subtypes of 15-LOX exist: 15-LOX1 (encoded by *15ALOX* gene) and 15-LOX2 (encoded by *15ALOXB* gene). Arachidonic acid (AA) is the major substrate for 15-LOX2, whereas 15-LOX1 prefers linoleic acid as substrate but could also metabolize AA. 15(S)-HETE is the major metabolite of AA formed by 15-LOX2 and 15-LOX1.

Recently we have demonstrated that progression of human renal cell carcinoma is associated with enhanced expression and activity of 15-LOX2.[@R9] RCC tissues are frequently infiltrated with CD45+CD11b+CD68+HLA-DR+ tumor-associated macrophages (TAMs). TAMs seem to be central players in deregulated eicosanoid production observed in RCC because they secrete the highest levels of major 15-LOX2 arachidonate metabolite 15(S)-HETE and highly expressed 15-LOX2 at both gene and protein levels. Isolated TAMs produce substantial amounts of pro-inflammatory chemokine CCL2 and immunosuppressive cytokine IL-10. Co-incubation of TAMs with autologous T lymphocytes resulted in dramatic (4--10 fold) increase of IL-10 production. Remarkably, inhibition of lipoxygenase activity significantly reduced secretion of CCL2 and IL-10 by TAMs, and also prevented TAM-mediated induction of IL-10 in T cells. In addition, TAMs were able to induce tolerogenic transcription factor FOXP3 and inhibitory receptor CTLA-4 in T lymphocytes. However, the ability of TAMs to convert T cells into FOXP3+ T regulatory cells or induce CTLA-4 did not depend on 15-LOX2 activity. It would be important in further studies to delineate the mechanism by which TAMs induce FOXP3^+^ T regs in kidney cancer.

Cancer therapy and immunomodulatory therapy of RCC is less effective in treating large tumors partly due to immune suppression associated with advanced metastatic cancer disease. Our data suggest that tumor-associated macrophages play an important role in the development of immune suppression and T cell tolerance in human RCC through secretion of immunosuppressive factors and induction of immune unresponsiveness in T cells. We demonstrated that immune suppression in RCC is closely relates to deregulated eicosanoid metabolism in the tumor microenvironment. [Figure 1](#F1){ref-type="fig"} provides a schematic overview of the contribution 15-LOX2-expressing tumor-associated macrophages in immune dysfunction in patients with kidney cancer. This figure illustrates that macrophages infiltrating human RCC have a significant impact on cancer inflammation via CCL2-mediated recruitment of monocytes to the tumor site[@R10] and inhibition of generation of anti-tumor immune response via secretion of IL-10 and also by conversion of T cells into T regs.

![**Figure 1.** Tumor-associated macrophages contribute to the cancer immune suppression and cancer inflammation in RCC via enhanced 15-LOX2/15-S-HETE pathway. Enhanced 15-LOX2 activity and elevated levels of eicosanoids of RCC tumor-microenvironment enable increased production of pro-inflammatory chemokine CCL2. Elevated levels of CCL2 in tumor lead to migration of CCR2-expressing monocytes from peripheral blood to the tumor. In tumor tissue recruited monocytes differentiate in 15-LOX-expressing tumor-associated macrophages (TAMs). High 15-LOX2 expression/activity in TAMs results in elevated secretion of arachidonate metabolites and increased production of IL-10 and CCL2 by TAMs and T cells. In addition, TAMs efficiently convert T cells into FOXP3^+^ T regs. Together, elevated levels of IL-10 and T regs promote local immunosuppression and T cell tolerance in RCC tumor microenvironment.](onci-1-249-g1){#F1}

Our results suggest that manipulation of deregulated metabolism of arachidonic acid and reduction of eicosanoid levels in tumor microenvironment represents an attractive approach to regulate both cancer-related inflammation and immune suppression in human cancers including RCC. Inhibition of 15-LOX2 activity could potentially synergize with existing RCC immunotherapy such as IL-2, IFNα or dendritic-based therapy thereby enhancing its therapeutic effect and improving overall survival of cancer patients.

Previously published online: [www.landesbioscience.com/journals/oncoimmunology/article/18502](http://www.landesbioscience.com/journals/oncoimmunology/article/18502/)


Q:

profile connect_time is taking time more then useal

I have assigned the below profile on the user that I am logged in
-- Create profile
create profile APP_USER limit
  connect_time 1;
-- Add users to profile
alter user scripts profile APP_USER;

however the below execution is taking normal time( 106,321 seconds)
declare var number(14);
begin
select count(1) into var from ort;
select count(1) into var from ort;
select count(1) into var from ort;
end;
/

shouldnt be 60 seconds ? and yes I am able to run queries afterward

A:

the Resource_Limit was set to off , it should be changed to true.
Alter system set Resource_Limit = True
/
show parameter resource_limit
/

Then I loged in into the database again , and it worked.


York County
A GLAUCOUS GULL was seen at the Saco Yacht Club at the end of Front Street in Saco on the 1st. On the 30th, a COMMON MURRE was seen from East Point Sanctuary in Biddeford. A return of WHIP-POOR-WILLS and GRASSHOPPER SPARROWS to the Kennebunk Plains was reported on the 6th.

Greater Portland
A WHITE-FACED IBIS was reported from various locations around the Scarborough Marsh throughout the week.

Lewiston-Auburn
Word finally got out on the 6th of a NORTHERN LAPWING in a field at the corner of Carpenter Road and Range Hill Road in Poland although it was reported to have been present since the 3rd. The bird was last seen flying northeast from this location on the evening of the 6th.

Kennebec River Valley (Augusta-Waterville)
A LOUISIANA WATERTHRUSH was reported singing from Vaughn Woods in Hallowell on the 28th and 29th. A SANDHILL CRANE was seen flying over Lower Togus Pond in Augusta on the evening of the 6th. Three SANDHILL CRANES were seen along Route 2 in New Sharon on the 1st. A high of five ICELAND GULLS on the 2nd and 2 LESSER BLACK-BACKED GULLS

Penobscot Bay
Uncommon in this area, a FIELD SPARROW had been visiting a Sedgwick feeder for three days as of the 29th.

Downeast
A GRAY-CHEEKED/BICKNELL’S THRUSH was reported from the Mount Desert High School Ridge Trail on the 4th. An adult RED-HEADED WOODPECKER was seen again on the 1st at a private yard in Bar Harbor.

Northern Maine
A pair of REDHEADS continued at Lake Josephine on the 5th.

Support Maine Audubon by having your own Birdathon team or pledging one of the staff teams, http://maineaudubon.org/events/birdathon/pledge/


Military history of Iceland

This is a brief overview of historical warfare and recent developments in Iceland.

Settlement and commonwealth

In the period from the settlement of Iceland, in the 870s, until it became part of the realm of the Norwegian King, military defences of Iceland consisted of multiple chieftains (Goðar) and their free followers (þingmenn, bændur or liðsmenn) organised as per standard Nordic military doctrine of the time in expeditionary armies such as the leiðangr. The armies being divided into units by the quality the warriors and birth. At the end of this period the number of chieftains had diminished and their power had grown to the detriment of their followers. This resulted in a long series of major feuds known as Age of the Sturlungs in the 13th century. During and before the war more than 21 fortresses were built.

The battle consisted of little less than 1000 men with the average casualty rate of 15%. This low casualty rate has been attributed to the blood-feud mentality that permeated Icelandic society, which meant that the defeated army could not be slaughtered honourably to a man. As well as the requirements of Christianity to get a pardon from a cleric for each fiend smitten, which resulted in only people of low class taking care of executions. While executions after battle were uncommon, they were extensive when they happened. See, for instance the battle of Haugsnes with about 110 fatalities, Flóabardagi with about 80 fatalities on one side and unknown on the other and the battle of Örlygsstaðir with up to 60 fatalities including executions. These three battles, or skirmishes as they would be called in a European context add up to 250 fatalities, so these three encounters alone add up to almost 6 of the average killings of 7 per year in the period 1220–1262. Years could pass without killings.

Amphibious operations were important part of warfare in Iceland in this time, especially in the Westfjords, while large naval engagements were not common. The largest of these was an engagement of a few dozen ships in Húnaflói known as Flóabardagi. One side employing smaller longships as well as boats and the other large Knaars, other larger merchant ships and ferries. Although neither side expected to do battle at sea, the battle was fought in a fairly standard way for the time, the ships being bound together, starting with archery and rock throwing, then spear hurling and ending in a melee all over the fleet, ships being exchanged by each side many times.

At first the chieftains relied primarily on peasant levies but as the war progressed and Norwegian military influences became more pronounced, their personal retinues expanded and became more professional. At the end most of the chieftains had been slain and only one of the original chieftains who started the war remained. It had nonetheless become evident that no one chieftain was powerful enough to vanquish all the others and ensure peace. This led the Icelandic betri bændur (better farmers or farmer leaders) of the South, North and Western Iceland to submit to the Norwegian crown and the Alþingi in 1262. Two years later in 1264 the Lords of Eastern Iceland, the Svínfellingar, submitted as well, but the Eastern Region had completely escaped the ravages of war, mostly because of its geographical barriers of wastelands, mountains and glaciers.

Union with Norway

Peace barely ensued as the Norwegian King had little capacity to enforce his will over the Atlantic Ocean, his navy, although the most powerful Atlantic navy at the time was too small to carry big enough invasion force all the way to Iceland. The native Nobles continued to maintain their elite troops, which were called sveinalið while the sýslumenn (sheriffs), most of which were noble descendants of the chieftains, maintained soldiers or sveinar for the defence duties that had been delegated to them by law. All inhabitants of a sýslumaður´s fief were obligated to follow them in battle against invaders.

The king rarely asked for expeditionary forces to help defend Norway, although Icelanders in Norway had been obligated to help Norwegian defences since the early 12th century. There are however a few documented occasions of Icelandic expeditionary armies coming to the king's aid.

As the church became more powerful its bishops and priests became more militant: at the peak of their power the two bishops could command armies consisting of over 6% of Iceland's total population. The Bishops' own sveinar could expect to become priests after their military service. The two bishops became de facto Ecclesiastical Counts or Kirkjugreifar, responsible for law enforcement and overall command of military defences. Icelandic noblemen became wary of the Bishops' powers in the late 15th century and protested. During the 15th century, when English traders and fishermen started to come to Iceland, it became a common practice among chieftains to buy cannons for defence against foreign ships and for internal conflicts. Other firearms, such as the hand gonne, known as haki or hakbyssa in Iceland, became popular as well.

Lutheranism

Since the king of Denmark had embraced Lutheranism in the early 16th century he had campaigned to convert his realms from Catholicism to Lutheranism. In the 1540s it was Iceland's turn: Lutheran bishop was elected as the bishop of Skálholt diocese and bitter conflict ensued. Although the bloodshed didn't come close to that in the Civil War fought in the 13th century it was still considerable as the bishops fielded armies of thousands, and even fought at Alþingi.

In a bid to isolate Skálholt, Iceland's last Catholic bishop, Jón Arason of Hólar, attempted to cut its lines of communication to the Westfjords by invading the lands of Daði Guðmundsson í Snóksdal. Although initially successful in capturing Sauðafell he was later defeated by Daði's army and captured with his sons. Jón Arason and his sons were then transported to Skálholt and beheaded there in 1550. A year later a Danish mercenary force mostly consisting of Landsknechts arrived to support the policy of conversion. Although no open warfare continued, the Danish king was still wary of an insurrection and ordered the destruction of all Icelandic arms and armor. Further mercenary armies, consisting of Landsknechts,  are sent to carry out these orders over the following years. After that starts a period where Royal Danish forces are responsible for the defence of Iceland. The Royal Dano-Norwegian Navy patrols the coasts of Iceland, but mostly to prevent illegal trading rather than piracy. Some Icelandic sheriffs, however, manage to continue to maintain considerable retinues, especially in the Westfjords, where the Landsknechts were not as thorough in their search.

Pirate raids
The lack of weaponry among Icelanders made them more vulnerable to pirate attacks than before, although in some places, such as the aforementioned Westfjords, Icelanders managed to massacre foreign pirates. Icelandic officials complained about the raids in letters to the king and as a result many halberds were sent to Iceland by Royal edict. The halberd, known as atgeir or arngeir in Icelandic, became a signature weapon of Icelandic farmers. The king remained wary of the Icelanders, and refused to supply them with firearms. As most of the pirates were well armed with such weapons it made defence difficult. However some old guns and cannons still remained and could be used against their ships.

In 1627 Icelanders were shocked at the inability of the Danish forces to protect them against Barbary corsairs who murdered and kidnapped a large number of people. In some places Danish troops fled from the raiders, but the Captain (Höfuðsmaður) of Iceland, who was the highest-ranking military officer and overall governor of Iceland, managed to defend Bessastaðir by hastily building fortifications and damaged one of the raiding ships severely with cannon fire. Some Icelanders were nonetheless angered that he didn't sink the ship despite it being stuck for 24 hours on a reef in front of the fortifications. As a result, Icelanders formed local militias with the king's blessing in places such as Vestmannaeyjar.

18th and 19th centuries

In the decades before the Napoleonic wars, the king declared his intention to send considerable amount of money to arm the Icelandic militias with muskets. However, his pledges were not fully fulfilled and in 1799 the few hundred militia-men in the South West of Iceland were mostly equipped with rusty and mostly obsolete Medieval weaponry, including 16th century halberds. When English raiders arrived in 1808, after sinking or capturing most of the Danish-Norwegian Navy in the Battle of Copenhagen, the amount of gunpowder in Iceland was so low that it prohibited all efforts of the governor of Iceland, Count Trampe, to provide any resistance.

In 1855, the Icelandic Army was reestablished by Andreas August von Kohl the sheriff in Vestmannaeyjar. In 1856, the king provided 180 rixdollars to buy guns, and a further 200 rixdollars the following year. The sheriff became the Captain of the new army, which become known as Herfylkingin, "The Battalion."
In 1860, von Kohl died, and Pétur Bjarnasen took over the command. Nine years later Pétur Bjarnasen died before appointing a successor, and the army fell into disarray.

Many have campaigned for an Icelandic standing army since the late 19th century, including Iceland's Independence hero Jón Sigurðsson, but except for the attempt in 1940 it has amounted to little.

Independence

In 1918 Iceland regained sovereignty as a separate Kingdom ruled by the Danish king. Iceland established a Coast Guard shortly after, but financial difficulties made establishing a standing army impossible. The government hoped that permanent neutrality would shield the country from invasions. But at the onset of the Second World War, the government, becoming justifiably nervous, decided to expand the capabilities of the National Police (Ríkislögreglan) and its reserves into a military unit. Chief Commissioner of Police Agnar Kofoed Hansen had been trained in the Danish Air Force and he moved swiftly to train his officers. Weapons and uniforms were acquired and near Laugarvatn they practiced rifle shooting and military tactics. Agnar barely managed to train his 60 officers before the United Kingdom invaded Iceland on May 10, 1940. The next step in the drive towards militarisation was to have been the training of the 300 strong reserve forces, but the invasion effectively stopped it.

Cod Wars

The Cod Wars, also called the Icelandic Cod Wars (Icelandic: Þorskastríðin, "the cod war", or Landhelgisstríðin, "the war for the territorial waters"), were a series of three confrontations from the 1950s to the 1970s between the United Kingdom and Iceland over fishing rights in the North Atlantic.

The First Cod War lasted from 1 September until 12 November 1958. It began as soon as a new Icelandic law that expanded the Icelandic fishery zone from , came into force at midnight of 1 September. After a number of rammings and a few shots fired between the Royal Navy and Icelandic patrol boats, Britain and Iceland came to a settlement, which stipulated that any future disagreement between Iceland and Britain in the matter of fishery zones would be sent to the International Court of Justice in the Hague. The First Cod War saw a total of 37 Royal Navy ships and 7,000 sailors protecting the fishing fleet from six Icelandic gunboats and their 100 coast guards.

The Second Cod War between the United Kingdom and Iceland lasted from September 1972 until the signing of a temporary agreement in November 1973. In 1972, Iceland unilaterally declared an exclusive economic zone (EEZ) extending beyond its territorial waters, before announcing plans to reduce overfishing. It policed its quota system with the Icelandic Coast Guard, leading to a series of net-cutting incidents with British trawlers that fished the areas. As a result, the Royal Navy deployed warships and tugboats to act as a deterrent against any future harassment of British fishing crews by the Icelandic craft, resulting in direct confrontations between Icelandic patrol vessels and British warships, which again included ramming incidents. After a series of talks within NATO, British warships were recalled on 3 October 1973. An agreement was signed on 8 November which limited British fishing activities to certain areas inside the  limit, resolving the dispute that time. The resolution was based on the premise that British trawlers would limit their annual catch to no more than 130,000 tons. This agreement expired in November 1975, and the third "Cod War" began.

The Third Cod War lasted from November 1975 to June 1976. Iceland had declared that the ocean up to  from its coast fell under Icelandic authority. The British government did not recognise this large increase to the exclusion zone, and as a result, there were again almost daily rammings between Icelandic patrol vessels and British trawlers, frigates and tugboats. The dispute eventually ended in 1976 after Iceland threatened to close a major NATO base in retaliation for Britain's deployment of naval vessels within the disputed  limit. The British government conceded, and agreed that after 1 December 1976 British trawlers would not fish within the previously disputed area.

NATO and the Cold War
Iceland's main contribution to the NATO defence effort, during the Cold War was the rent-free provision of the "agreed areas"—sites for military facilities. By far the largest and most important of these was the NATO Naval Air Station Keflavík, manned by American, Canadian, Danish, Norwegian and Dutch personnel. Units from these and other NATO countries also are deployed temporarily to Keflavík, and they stage practice operations. Many of these practices were anti-submarine warfare patrols, but these exercises were halted when the P-3 ASW aircraft were withdrawn from Keflavík.

Iceland and the United States regarded the U.S. military presence since World War II as a cornerstone to bilateral foreign/security policy. The presence of the troops was negotiated under a treaty known as the Agreed Minute.

Talks about the American presence were restarted as of 2005, since the U.S. government was keen on deploying its troops and equipment to parts of the world with more pressing need for them. Proposals by the Icelandic government included a complete Icelandic takeover of the Airbase, as well as replacing the Pavehawk rescue helicopter unit with a detachment from the aeronautical half of the Icelandic Coast Guard, in exchange for the continued stationing of the four F-15C interceptors in Keflavík.

On March 15, 2006 the U.S. government announced that the Iceland Defense Force would be withdrawn by the end of September 2006. The last American troops left on September 30, handing control of the Keflavík base over to the Sheriff of Keflavík airport, who was to be in charge of it on behalf of the Ministry for Foreign Affairs.

American withdrawal

On September 26, 2006 the Government of Iceland released a document containing Iceland's response to the withdrawal of American forces. It included plans (a) to create a Security and Defense authority to oversee all security organisations in Iceland, including Police and Coast Guard; (b) to increase the capabilities of the Coast Guard by purchasing vessels and aircraft; (c) to create a Security or Secret service; and (d) to establish a secure communications system spanning the whole country. MP Magnús Þór Hafsteinsson of the Liberal party voiced his party's willingness to raise a standing army, in agreement with views expressed by Björn Bjarnason Minister of Justice and Ecclesiastical affairs.

The Icelandic Defence Agency (Varnarmálastofnun Íslands) was founded in 2008 under the Minister for Foreign Affairs. The Agency was to consolidate functions previously served by NATO forces at Naval Air Station Keflavik, such as maintaining defense installations, intelligence gathering and military exercises. An initial budget of $20 million fell to $13 million in 2009 as the Icelandic economy suffered a crisis. On 30 March 2010, the Icelandic government announced it would legislate to disband the Agency and put its services under the command of the Coast Guard or National Police. To save money and to restore the primary role of the Icelandic Coast Guard in defense, the Defence Agency was shut down on January 1, 2011.

Iceland Air Meet 2014 hosted NATO and other Nordic countries for the first time.

See also

History of Iceland
Borgarvirki
Battle of Haugsnes
Battle of Sauðafell
Battle of Víðines
Battle of the Gulf
Battle of Örlygsstaðir

References

Further reading
Þór Whitehead, The Ally who came in from the cold: a survey of Icelandic Foreign Policy 1946–1956, Centre for International Studies. University of Iceland Press. Reykjavík. 1998.

External links
Icelandic Coast Guard.
Icelandic National Police.
Iceland Air Defence System.
Ministry of Justice and Ecclesiastical Affairs.
Ministry for Foreign Affairs.


Discovery of β-glucosidase inhibitors from a chemically engineered extract prepared through ethanolysis.
A series of vegetal extracts have been chemically altered by ethanolysis. The effect of the reaction on the inhibition of the enzyme β-glucosidase properties of the mixtures was studied using thin layer chromatography (TLC) with biodetection. Glucosidase inhibitory activity guided fractionation of one of the produced chemically engineered extracts led to the isolation of apigenin and ethyl p-cumarate. Both compounds were generated during the chemical modification step.