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Children and How They Came into Fashion on Printed Textiles between 1770 and 1840

In the eighteenth century in England, a new technique for printing on fabric was perfected, which made possible the reproduction of large designs by using the principle of engraving. Imported into France in the 1770s, copperplate printing (term used at the time to denote these single-colour prints in red or blue) helped the rapid development of monochrome images on fabrics for interior decoration, with figurative images borrowed from a certain style of painting and prints.

Well before manufacturers invented fabrics for children, the textiles known as toiles de Jouy made much use of the child, from new-born to school-age, in its figurative prints. Putti, little cherubic babies, were a frequent motif in compositions that included the same decorative procedures as paintings of interiors and decorative arts. But in the late eighteenth century, a genuine vision of childhood appeared in some compositions. These images expressed the influence of the Age of Enlightenment that changed the perception of relationships within the family, notably between the mother and her children. At this time, it was education rather than childhood that became the real challenge for the philosophers. The making of the 'new man' now came by way of childhood, at the time when the child is seen as an entirely separate being and an adult-to-be.

The feeling of childhood, to recall the words of Philippe Ariés and, more broadly, the preoccupations which surrounded the young child, are reflected in the printed textile [START_REF] Ariès | L'enfant et la vie familiale sous l'Ancien Régime[END_REF]. At the end of the eighteenth century, these representations evolved into the placing of the child at the centre of the family, reflecting the arrival of a middle-class society in which the child's education became a real focus.

Between the second half of the eighteenth and first half of the nineteenth centuries, the presentation of childhood was changing, the fabric makers following the taste and motifs spread by the print process. So how did this transformation come about in printed textiles and what were the sources of imagery for the designers. Starting with the biggest French manufacturers between 1770 and 1840, we will see how the idea of childhood was spread via the fabrics designed to persuade the biggest number of buyers to choose them for their interiors. And we will see how, in the nineteenth century, these designs promoted a real dialogue centred on the child.

The numerous exhibitions devoted to the depiction of childhood in textile production demonstrated that specialised fabrics for children, in both furnishing and clothing, did not exist before the end of the nineteenth century (Exhibition 2011 and[START_REF] Exhibition | Motifs d'enfance, exhibition at the museum of Bourgoin-Jallieu[END_REF]. In the eighteenth century, representations of children remain rare and do not form part of a particular genre. From the 1770s onward, single-colour copperplate prints with figurative motifs, designed for interior decoration, helped to introduce images of childhood on textiles. Because they were printed in large quantities, the makers favoured fashionable themes and motifs, often spread by printing. The compositions remain reflections of taste in decorative painting or current literary and artistic trends. The child is thus often confused with the putto, or cherub, a widespread motif in romantic compositions. So before fabrics for children were developed, the childish figure was ever-present in figurative prints, but for decorative reasons, they were children in pastoral scenes or, in the compositions of earlier times, cherubs or putti.

Nevertheless, in certain designs new representations of childhood appeared in textiles, echoing the iconography of genre painting, spread by printing. The design named Jeux d'Enfants (Children's Games) (fig. 1) printed at the Jouy factory between 1770 and 1783, bears witness to the interest in the child's life and forms a new decorative theme in furnishing textiles.

The composition is arranged around three scenes of children playing in a park, who become the central figures and subject of the design. This illustration reflects this feeling of childhood, as an awareness of its special place among the gentry, who notably passed their time inventing games. Despite the simplicity of the drawing or design, this example reveals the switch in taste to a new image of childhood, as spread by printmaking. At the same time, the use of these cloths flourished in bedrooms and boudoirs, the private spaces of the home where women played their role in the bosom of the family. But this composition does not illustrate the emergence of a new genre of motifs in textiles. It appears as a rare example in which the child is presented mimicking adults, as imagined in pictorial tradition since the sixteenth century [START_REF] Branden | Les jeux d'enfants de Pierre Bruegel[END_REF]. This composition adapts the fashionable taste for parodies of children in the decorative arts and paintings of the eighteenth century, notably on porcelain and china. In reality, we have to wait for the mid-nineteenth century for the theme of children's games to become a familiar subject on printed textiles.

A VISION OF CHILDHOOD IN THE EIGHTEENTH CENTURY

In France, between 1770 and 1780, among the big manufacturers, the printing of large figurative designs was marked by the taste for genre painting, particularly Flemish painting, the prints of which assured its spread into the affluent classes. The artists seized on these examples of popular family scenes, of peasants breast-feeding or surrounded by children. The representation of children in the first fabrics with figures is based on these models, which feature village feasts, animal and farm scenes with children.

Childhood and family scenes in early printed textiles

In the second half of the eighteenth century, the child becomes a regular protagonist in the Flemish or pastoral-style scenes which characterise figure paintings. He or she is shown among adults in rural scenes that evoke a nurturing and beneficial lifestyle. The female figure, mother or nursemaid, surrounded by children, from now on plays a part among the figures commonly seen on these cloths. The role attributed to the mother in the education of the young child, notably since the ideas developed by Jean-Jacques Rousseau in his 1762 work L'Émile ou De l'éducation surely explains these representations. Rather than the child, it is the education in the countryside and the place accorded the mother, which became a source of motifs for the designers. In Jouy, several compositions juxtapose scenes of dance, of laundresses, fishermen, animals etc. Some images evoke the country life as in this drawing (fig. 2), near the end of the 1770s where the childhood presence is limited to a female farm worker accompanied by a baby and a young child.

From 1782, this maker sold a cloth titled La fête flamande (The Flemish Party) (fig. 3), depicting a string of scenes of feasting and drinking, directly borrowed from the prints of Flemish and Dutch artists. The scene where a mother breastfeeds her child is only a secondary detail in a composition focussed on the party, the wine and the good food, a frequent theme in fabrics with figures of this period.

This composition was such a success that the maker, Oberkampf, commissioned a new design from the painter Jean-Baptiste Huet: with a placing and arrangement a bit like that of the drawing I sent you in regard to the number, the proportion and size of the figures but of various subjects, different from those of the stated project." (Archives of the factory at Jouy, Archives Nationales (AN), Centre des Archives du Monde du Travail à Roubaix (CAMT), 41AQ83.930.).

From 1783, the animal painter Huet, who specialised in pastoral scenes, became the chief designer of figurative compositions for this manufacturer. In creating La nouvelle fête flamande (The New Flemish Party) (fig. 4), printed from 1797, he continued in the style inspired by the Flemish painters of the eighteenth century while keeping the flavour of the romantic countryside. Again he takes up the central motif of the drinking trough, giving more importance to the décor and architecture. Above all, he multiplies the motifs in an idyllic vision of country life -scenes of ball games, children playing with a goat, farm activities like butter-making, transporting cows etc. The artist favours these picturesque scenes -but grants a new place to the child. The scene in The Flemish Party with the breastfeeding mother is transformed into a real family tableau.

In the eighteenth century, the representation of childhood and the family in furnishing textiles took on an aspect, above all, of family scenarios, popular in Flemish painting, where the child appears in the world of adults. The taste for this type of scene marked these prints for a long time, since this style was perpetuated and continued to please certain consumers up to the start of the nineteenth century when the arts became definitively stamped by the neo-classical trend. The New Flemish Party was marketed between 1799 and 1809, the date on which the printing was stopped due to wear-and-tear of the copper plate -even though the design was still in demand with traders in 1810 (AN, CAMT, 41AQ91.322).

The benefits of nature for the child

In the eighteenth century, the manufacturers' designers produced more and more scenes of fishing, hunting, harvests and young female farm workers accompanied by children, in an idealised vision of the countryside and the ways of village life. This taste for nature, seen as beneficial and nurturing, where the figures are scattered in little scenes, contributed to the categorising of these figurative monochrome prints by the manufacturers. At Jouy, the work of Jean-Baptiste Huet was distinguished by pastoral scenes depicting groups of country folk that often included children, enjoying the fruits of the land among the farm animals. In 1784, to celebrate the American War of Independence (fig. 5) the artist adapted the principle of decorative painting in arabesques where real pictures of country life were featured: for instance, a farmworker surrounded by young children who are feeding the barnyard animals. In La ferme (The Farm) (fig. 6) created around 1795, Jean-Baptiste Huet continued in the landscape tradition where scenes of fishing, feeding animals in the farmyard or milking the cows, a mule accompanying the herd, were again motifs borrowed from Dutch landscapes. The children are from now on ever-present, nourished by the benefits of nature, drinking fresh milk in the dairy in their mothers' arms, playing in the midst of adults.

In the printed textile, the artist went on linking childhood to the countryside with representations of family life, but introducing a new sensitivity influenced by the painting of the French artist, Jean-Baptiste Greuze. The cloths reflect the country way of nurturing and also echo, in a certain way, the philosopher Rousseau's idea of 'natural education'prescribing country life for the young child where, in contact with nature, he can grow and develop feelings, as well as make simple, spontaneous judgements. The pastoral theme set the scene for childhood -farmer's wife and children or children with a nursemaid, often associated with romantic scenes, fashionable on figured toiles.

In Le mouton chéri (The Baby Sheep) (fig. 7) printed by the manufacturer Favre Petitpierre at Nantes around 1785, the composition is above all devoted to love, with a string of romantic scenes inspired by prints. Children appear in several scenarios, near a couple playing blind man's buff, with farmworkers or nursemaids. The representation of childhood in pastoral and romantic settings lasted until the end of the century, as in La balançoire ( The Swing) (fig. 8) printed at Jouy in 1797. In this print, Jean-Baptiste Huet continues his agricultural style with amusing scenes where animals are the leading actors: a dog pursuing a cat, a wolf attacking a flock. He updates the pastoral theme by giving importance to the swing scene in the romantic spirit of etchings of see-saw games. In this depiction, at once romantic and charming, the children look at the workings of the farm among the animals or play at riding a dog on a leash. Again, such sketches present an idealized vision of country childhood.

The expression of maternal love

In the eighteenth century, the child became an object for concern and emotional investment, which from now on would be openly shown, as the family became a "necessary place of affection" (Ariès and Duby 1980). This feeling manifested itself in the relationship with the mother, who exuded the tenderness and love needed to make the child bloom. Furnishing fabrics favoured a representation of childhood in nature, echoing ideas promoted by Rousseau. The writings of the philosopher spread the idea that breast-feeding was an act of nature and a demonstration of motherly love that should be favoured. But the scenes of breast-feeding in The Baby Sheep (fig. 7), The Flemish Party (fig. 3) and The New Flemish Party (fig. 4) reflect the interest in village ways rather than in this new practice, widespread in England, which influenced an enlightened few in France [START_REF] Soupel | Les âges de la vie en Grande-Bretagne au XVIIIe siècle[END_REF]. These printed scenes allude, above all, to being nurtured in the countryside, a practice which was extended in the second half of the century to the merchant and artisan classes of the towns, preserving an image of childhood spent in nature (even if the reality was very far from this ideal vision). The mother paying a visit to her child became a subject for paintings, and the idea spread through prints. These representations show the new solicitude for the very young and express maternal love. In The Swing (fig. 8) one can distinguish, on one side, a farm worker busy milking goats with a young child. On the other, a better-dressed young woman who accompanies children playing at riding a dog, suggests a nursemaid or indeed a mother and her children.

L'éducation à la champagne (Education in the country) (fig. 9), a composition created at Jouy in the 1780s, reflects these practices but also this new attention to childhood where the little one is the object of much attention while learning, in this instance, to walk. The clothing and placing of the figures, the mother sitting beside a young boy who wants to play with a kite, opposite the nursemaid, are again images of a mother admiring her young child, widespread in printmaking.

A project designed at the factory at Jouy again takes up the theme of the stages of childhood (fig. 10). A swirly border frames a scene conceived as an allegory of the evolution from babe-in-arms to young child, as described by Rousseau. The naked baby playing on a rug illustrates the new enthusiasm for bodily freedom: No sooner has the child left its mother's breast and no sooner does he enjoy the freedom to move and stretch his limbs, than he is given new boundaries. He is swaddled with his head constrained, legs straightened, arms at his sides. He is wrapped in linens and bandages of all kinds, which don't allow him to change position. He is swathed so tightly he can barely breathe and has to be put to bed on his side so that the liquids that pass from his mouth can fall out of their own accord since he would not have the freedom to turn his head sideways to ease the flow! [START_REF] Rousseau | Émile ou de l'éducation[END_REF] If the naked baby can be seen as an allegory, the characters play out family scenes of mothers with children, so beloved of genre painting of the eighteenth century [START_REF] Blumenfeld | Margeurite Gerard et la peinture de genre de la fin des années 1770 aux années 1820[END_REF].These two compositions reflect the interest in images of mothers with their children in well-to-do social circles, evident in the dress of the young women. Their attitudes and gestures illustrate the care and love which is shown for the small child. From now on, childhood is a period of life which calls for games adapted to each age: a rattle for a baby, a hobby horse for a small boy whose clothes reflect the new fashions in children's dress, the boy is dressed in a sailor-suit, an English fashion in the 1780s. The design incorporates the new 'Greek' trend with revellers, nymphs, cherubs riding lions, in a spirit still marked by the romantic, as seen in the pair of doves. The surrounding drawing, with a dash of love and the gods thrown in, forms a decorative frame for a scene expressing motherly love, reflecting the importance given to the child in the bosom of the family. The composition could justly be called the feeling of childhood.

BUILDING AND EDUCATING THE CHILD, FURNISHING TEXTILES A DÉCOR WITH MESSAGES

From the end of the eighteenth century, in some compositions the purpose of interior décor changed, the aspect of countryside charm giving way to a vision turned towards family values. The instructive aspect came into favour in scenes that reflected the arrival of a middle-class society. Great literary successes became frequent themes, with furnishing textiles featuring real picture stories. The sudden enthusiasm for literary themes illustrates the evolution of a lifestyle, as if bedroom décor must also take part in a child's education, even if such specialised fabrics did not yet exist. In offering a scenario of childhood, which passed from picturesque scenes to an instructional view of the family, the makers adapted to the buyers' taste and the transformation of the printed textile market. In the 1830s, the printing of figurative cloths became popular, with affordable products and decorative repeated patterns. Educational motifs were favoured, furnishing fabrics became vehicles for moralising images, often acted out by the family. Around 1840, the motifs continued to promote family life, with the child the subject of the story.

The child at the heart of the family

In the eighteenth century, family representations in painting and prints showed that the "modern family", for a long time exclusively the nobility, now included the middle class [START_REF] Kayser | L'enfant chéri au siècle des Lumières : après l'Emile, catalogue musée Marly-le-Roi[END_REF]. The style of figurative textiles endured, using this abundant family iconography. At the Favre Petitpierre factory in Nantes between 1795 and 1800 (fig. 11), the designer borrowed his scenes from fashionable prints and arranged them in medallions or contained them in frames, like engravings hung on a wall. The central scene shows the child at the heart of the family as copied from the etching of L'enfant chéri (The darling child), after Fragonard and Marguerite Gérard (Margerand 2001). But the need to adopt the oldfashioned style justifies the other scenes where relations between the child and the adults are evoked via the theme of Venus and love.

In La fête aux enfants (The children's party) printed in a Nantes factory around 1795, we again see romantic scenes in a rural setting where the main scenario is no longer about childhood but about the family (fig. 12). The composition transposes representations of well-to-do families whose ideal is from now on personified by a group formed by parents and their children. The spread of family feeling, for long the preserve of the elite, becomes a social norm, explaining its place in furnishing. If these designs still kept their picturesque countryside character from the earliest figured fabrics, they heralded the evolution of representations of the family in an uplifting vision in the nineteenth century.

Representation of the family

In the nineteenth century family feeling, which had already taken hold within the middle classes, extended into the countryside. But the concept of family evolved, from now on the iconography celebrates not only the parents with their children but also the image of the patriarchal family, gathering together several generations [START_REF] Gourdon | Histoire des grands-parents[END_REF]. The spread of this family feeling in society is shown by the modification of the family group that extends beyond parents and children. In the textile industry, the 1820s are marked by an evolution in the style of figured prints, which became more affordable and appreciated by the mass market.

The designers made variations of the same decorative scheme: two scenes in a five-part sequence, framed by garlands of leafy flowering plants, which they adapted to each new composition. The Indian factories in Normandy specialised in this kind of print, which favoured decorative themes for less sophisticated consumers. The fabrics became supports for instructive motifs, romantic subjects giving way to historic accounts, biblical scenes or pictures of family life. The theme of marriage was particularly strong, with numerous versions created of the bourgeois betrothal at a village wedding (Dore 2007). Childhood does not disappear from furnishing fabrics but its representation is confirmed in family settings. In this toile from a Rouen or Bolbec factory around 1830-1840 (fig. 13), the designer juxtaposes a village dance, no doubt a wedding, and a family scene in a Normandy peasant home. A new image of the child appears: the dominant figures are no longer the mother with the child, but the patriarch in his armchair who makes the grandson dance to the sound of his violin. In these toiles the child becomes one of the figures in a family scene where he appears cosseted in the midst of an extended family, again underlining the theme of the generations.

In the 1830s, these cloths reflected social practices and cultural images. The child's development now progressed via the education he received within the family circle. The benefits of family life replaced those of nature with its scenarios of parties, meals and prayer. Le goûter et la prière (The afternoon tea and prayer) (fig. 14), a design printed by the Rouen manufacturer Belloncle et Malfeson, reproduces some very well-known prints by Mallet (Dore 2007). The composition juxtaposes two scenes, on one side children with their mother gathered around for tea, a childhood meal; on the other, the saying of grace, the prayer recited by the father before the meal, a family scene. Les costumes normands (The costumes of Normandy) (fig. 15) a composition which celebrates an idealized life of peasants around family values, also features a scene of a meal begun with the saying of grace. Philippe Ariès analyses the spread of prints showing the saying of grace by the child as the manifestation of the growth of three feelings: "Piety, the feeling of childhood (the smallest child) and the feeling of family (the gathering at the table)" [START_REF] Ariès | L'enfant et la vie familiale sous l'Ancien Régime[END_REF].

The appearance of these family meals with the young child saying grace have to be seen in the context of the evolution of the iconography of the furnishing textiles of the nineteenth century which focus on uplifting decoration. The Rouen factory made cloths a real base for didactic and moralising messages.

In Alsace, around 1840, Georges Zipélius (1808-1890), a specialist designer for the printed textile and wallpaper industry, produced a representation of childhood in popular imagery [START_REF] Francès | Georges Zipélius, un exemple mulhousien du XIXème siècle » maîtrise d'histoire de l'art[END_REF]. The same decorative processes of the Rouen manufacturers were applied to frame two little scenes. The child was above all a participant in amiable family scenes where the individuals in a house play with one another-the grandmother, father and mother. The vision of the family and the home, an inspirational place for the education of children, is transformed-in the personal decorative vocabulary of the designer-in a charming, almost playful vision where children play among themselves or with the farm animals. His designs sometimes took a more uplifting character as in this composition (fig. 17) where the grandmother gives a lesson to a group of children while the grandfather corrects one of them. But, in all, it is not a moralising message-the designer's images are charming and some a little naïve. In another composition (fig. 18), Georges Zipélius uses the scene of a village school for boys and the teaching at home received by the girls. Children's education began with instruction at the moment when the Guizot law of June 1833 introduced primary teaching for all, each commune having to open a school for boys. But while the subject took on a didactic theme, it was treated in the same style as his other compositions. The teaching of girls was shown as taking place within the family circle at home, while the boys' class took place in a scene approaching caricature. Rowdy pupils surround the old teacher asleep in his chair, a lone child tries to read his lesson, disturbed by his classmates. The designer prefers the image of a noisy and undisciplined childhood, far from the aims of public teaching, reflecting the reality of schools as "places where children are pushed about, in a mixed, rough-and-tumble crowd, with little desire to learn" [START_REF] Becchi | Le XIXe siècle[END_REF]. We again find this excited atmosphere linked to the theme of children's games on leaving the class in real disarray (fig. 19 detail). The designer looks affectionately on childhood as a moment of carelessness, not presenting the instructional and inspiring aspect of the toiles from the manufacturers of Normandy.

Children in furnishings

In the 1840s, the popularisation of these furnishing fabrics contributed in spreading an idealised image of the child, as distinct from adults, where he or she no longer appears at the centre of adult attention but in a state of listening to a lesson from grandmother or the teaching of a schoolmaster. The child leans towards his or her own world, with its games, independent of adults, an image already spread in painting, clearly visible in the famous picture, Les enfants de Hülsenbeck (The children of Hülsenbeck) by Otto Runge (1805, 131x 143 cm, oil on canvas, Kunstalle, Hamburg). This individualisation of the child is reflected in the evolution of practices: the generalisation of primary education, the arrival of the children's bedroom, development of games, which extended progressively from the affluent classes to the masses.

Georges Zipélius, prolific designer for the printed textile makers, presented a vision of childhood which foreshadowed the fabrics for the child at the end of the century. Certain designs on the theme of children's games were printed in the same years by the makers of Bolbec whose workshop had expanded beyond Alsace and proffered a pleasing and rather naïve picture of childhood (Dore 2007). At a time when teaching tracts valued playful activities as a means of educating the young child, the designer employed images of children playing in compositions where certain scenes were repeated: boys dressed as soldiers, the playground, girls dancing in circles (fig. 19), borrowed from the popular childhood imagery widespread by printmaking. The numerous versions give witness to the commercial success of these textiles. In some compositions he favours showing children in nature, often alone among animals; little scenes underlining the relations among siblings where the older ones, in the absence of the parents, take care of the youngest (fig. 20 and21). Childhood has become the real theme of these toiles, which present an image of the country at the same time instructive and idealised, very different from that of the rural scenes of the eighteenth century. With Zipélius, the vision of childhood is borrowed from popular imagery where the decorative and charming aspect is more important than the instructional, widespread in the printed toiles of the nineteenth century.

CONCLUSION

Between the eighteenth and nineteenth centuries, furnishing textiles underwent a considerable aesthetic transformation, going from large countryside designs to formularised compositions based on the same decorative principle. The textile industry did not escape the constraints of industrial production, which had to take into account the taste of consumers and the evolution of the market. From an upmarket clientele who appreciated pastoral scenes, the market widened towards a mass public who sought in these fabrics settings corresponding more to an ideal vision of the petite bourgeoisie the family, learning, games etc. It is certainly this evolution that the motifs reflect, rather than the appearance of the 'feeling of childhood', so dear to Philipe Ariès. If one refutes the change in mentality that the historian wanted to see, we can understand with hindsight that the manufacturers had taken into account the evolution in taste of their clientele. In the eighteenth century, the child was above all a motif which added charm to pastoral and romantic scenes. The few compositions which featured relations between mother and child, or parents around their children, remained rare, reflecting the taste for the scène de genre and how the designers had adapted this style for interior decoration.

In the eighteenth century, wallpaper manufacturers adapted certain compositions, inspired by family scenes in paintings, to spread this taste into interior decoration by offering wallpapers matching their figured textiles. In the nineteenth century, when the makers freed themselves from the influence of the printed textile, illustrations of childhood disappeared. In the panoramas where numerous figures were featured, the presence of children was rare, whereas the child figure was widespread in the illustrated press and in prints.

Figured textiles offered a standardised vision of childhood at a particular moment when family life and education prepared the child to become a good adult. This setting of childhood and family is a variation of painting where family representations exult in scenes of daily life and bourgeois hierarchies [START_REF] Becchi | Le XIXe siècle[END_REF]). In the mid-nineteenth century, the printed textile became a base from which to spread a social and educative message via interior décor, using a simplified talking point (the happiness of the home, games, education). These textiles took up themes developed in illustrated journals, fulfilling the expectations of the clientele [START_REF] Sadoul | Les origines de la presse pour enfants[END_REF].

None of these motifs was developed to please children. They were aimed at adults, trying to appeal to them by transposing popular imagery into a decorative language. If the child became the theme of the décor, it was mainly because these little scenes and their humour struck a chord with the consumers.

Aziza Gril-Mariotte

University of Haute-Alsace, researcher at CRESAT.


Generation from continuous waves of frequency combs with large overall bandwidth and tunable central wavelength B. Barviau, C. Finot, J. Fatome, G. Millot

We experimentally show that the combined effects of Raman soliton selffrequency shift with either compression of a sinusoidal beating or modulation instability lead to the generation of frequency combs with a spectral width higher than 100 nm and a central frequency shifted towards higher wavelengths.

Introduction: Generation of new optical frequencies in the 1.6-1.7 µm range is of high interest for a large variety of applications. In this context, starting from erbium-fibre based devices emitting in the 1.5 µm range, several techniques based on nonlinear effects in optical fibres could be used, such as wavelength conversion through four-wave mixing [START_REF] Nowak | Low-power high-efficiency wavelength conversion based on modulational instability in high-nonlinearity fiber[END_REF], generation of cascaded Raman

Stokes waves [START_REF] Benabid | Stimulated Raman scattering in hydrogen-filled hollow-core photonic crystal fiber[END_REF] or spectral slicing of supercontinuums [START_REF] Abeeluck | Continuous-wave pumping in the anomalous-and normal-dispersion regimes of nonlinear fibers for supercontinuum generation[END_REF]. However, those various approaches can suffer from serious drawbacks. Indeed, in the first case, the pump energy is equally spread between lower and higher wavelengths, thus leading to non-optimal efficiency for the 1.6-1.7 µm range.

For Raman emission, a restricted number of frequencies is allowed due to the large and fixed spectral spacing resulting from the Raman gain of the propagation medium, e.g. silica or gas filling a hollow-core photonic bandgap fibre. On the other hand when using a supercontinuum, initial energy is continuously spread out over a broad spectral range, thus leading to a relatively low spectral power density.

In this paper, we experimentally evidence an alternative approach exploiting the soliton self-frequency shift (SSFS) in order to tune the central frequency of two continuous or quasi-continuous waves [START_REF] Mamyshev | Generation of a high-repetition-rate train of praticaly noninteractiong solitons by using the induced modulational instability and Raman self-scattering effects[END_REF]. We will first expose the principle of the method before detailing the experimental device and the results obtained by two different alternatives.

Method principle: An attractive and flexible solution for shifting the wavelength of an optical wave is the use of intrapulse Raman scattering under which the central frequency of a wave is progressively shifted towards lower frequencies [START_REF] Gordon | Theory of the soliton self-frequency shift[END_REF]. However, as this process is only efficient for ultrashort pulses, it does not seem a priori suitable when continuous or quasi-continuous (nanosecond pulses) waves are considered. So, the issue was to find an easy way to convert two continuous waves into a train of sub-picosecond pulses. Two approaches are then feasible. The first one is based on the compression of a sinusoidal beat signal into a train of Gaussian transform-limited ultrashort pulses [START_REF] Fatome | 20-GHz-to-1-THz repetition rate pulse sources based on multiple four-wave mixing in optical fibers[END_REF]. For this technique, energy is initially equally divided between two wavelengths and harmonics develop through a multiple four-wave mixing process. In the second approach, energy is mainly concentrated into the pump wavelength, while a seed signal stimulates the generation of harmonics via induced modulation instability [START_REF] Tai | Observation of modulational instability in optical fibers[END_REF]. Once the train of ultrashort pulses is achieved, then it will be subject to the SSFS process.

In both approaches, we will generate at the fibre output a frequency comb with a central wavelength shifted toward higher wavelengths. The frequency spacing between the harmonics can be tuned by simply changing the frequency separation between the two initial continuous waves. It should be noted that the conversion of quasi-continuous waves into an ultrashort pulse train and the SSFS effect proceed in a single anomalous dispersive optical fibre.

Experimental set-up: The general idea to combine modulation instability and SSFS was numerically suggested in 1990 by Mamyshev et al. [START_REF] Mamyshev | Generation of a high-repetition-rate train of praticaly noninteractiong solitons by using the induced modulational instability and Raman self-scattering effects[END_REF] with the aim of filtering pedestals of ultrashort pulses. However, to date, no experimental implementation had still been carried out. We detail here the two experimental set-ups that we have implemented. The first approach (see Fig. 1) is based on the sinusoidal beat signal created by two continuous laser diodes spaced by 9 nm (external cavity lasers, ECL). An acousto-optic modulator makes it possible to slice long pulses (350 ns) which are then amplified by an erbium doped fibre amplifier (EDFA) with an average power of 1 W. A phase modulator is used in order to avoid deleterious effects of Brillouin backscattering [START_REF] Fatome | 20-GHz-to-1-THz repetition rate pulse sources based on multiple four-wave mixing in optical fibers[END_REF]. The continuous waves are then injected into a 900 m highly non-linear fibre (HNLF -nonlinearity 10 W -1 .km -1 ) with low anomalous dispersion (0.7 ps.nm -1 .km -1 ), reduced dispersion slope of 0.0072 ps.nm -2 .km -1 and attenuation of 0.7 dB.km -1 . Our second approach (see Fig. 2) relies on the use of 10 ns flat top pump pulses delivered by an erbium doped fibre laser.

The pulse profile is supergaussian (Fig. 2b) and has thus the advantage of not presenting any notable rebound [START_REF] Kuzin | Intra-pulse Raman frequency shift versus conventional Stokes generation of diode laser pulses in optical fibers[END_REF]. A peak-power of 17 W enables us to use a shorter segment of dispersion-flattened HNLF (90 m -same parameters as the fibre used in the first approach) as well as a seed pulse shifted by 25.5 nm. Let us note that for both approaches, in order to optimize the efficiency of the temporal compression of the initial modulation, we have used linearly polarised sources and carefully aligned the polarisations at the HNLF input.

Results:

The experimental results are presented in Fig. 3. In the case of the sinusoidal beat compression, 24 harmonics are generated between 1500 and 1710 nm, regularly spaced by 9 nm (Fig. 3a). In the approach based on induced modulation instability, 11 harmonics are obtained between 1450 and 1750 nm, regularly spaced by 25.5 nm (Fig. 3b). The signal-to-noise ratio measured with an optical spectrum analyser is higher than 17 dB. Thanks to the large spectral period of the comb, a single harmonic could be easily extracted with a band-pass filter in order to generate a frequency-shifted continuous (or quasi-continuous) wave. In both methods, the spectrum is shifted via intrapulse Raman effect towards higher wavelengths (dominating wavelength of 1689 nm and 1635 nm for the first and second method, respectively). The central wavelengths of the combs can be easily tuned by adjusting both initial frequency separation and powers launched into the HNLF.

Numerical integration of the generalized non-linear Schrödinger equation which governs the wave propagation has highlighted that the major effects limiting the performances achievable by both techniques are the third order dispersion and the initial signal to noise ratio. Moreover, building up of Raman amplified spontaneous emission can also partly explain the degradation of the output optical signal to noise ratio.

Conclusion:

We have experimentally studied the combined effects of the Raman soliton self-frequency shift with either beat signal compression or induced modulation instability. Two fully-fibered set-ups, relying exclusively on commercially available devices, have enabled us to generate frequency combs with a spectral width higher than 100 nm and a central frequency shifted towards higher wavelengths. The use of an additional contrapropagative Raman pumping would make it possible to extend the observed spectral shift [START_REF] Chesnut | Soliton self-frequency shift in highly nonlinear fiber with extension by external Raman pumping[END_REF].


PharmD Guillaume Monneret
email: guillaume.monneret@chu-lyon.fr

Fabienne Venet

Bart-Jan Kullberg

Mihai G Netea

ICU-acquired immunosuppression and the risk for secondary fungal infections

Keywords: immunosuppression, sepsis, ICU, fungal infections, mHLA-DR

Indeed, it is now postulated that sepsis initiates a complex immunologic response that varies over time, with the concomitant occurrence of both pro-and anti-inflammatory mechanisms alternately predominating [1,2]. After a short pro-inflammatory phase, septic patients enter a stage of protracted immunosuppression. Importantly, similar mechanisms have been observed in patients presenting with a systemic inflammatory response syndrome (i.e., after trauma, burns, major surgery, pancreatitis) suggesting that most intensive care unit (ICU) patients, at least transiently, develop features consistent with severe immunosuppression [1,2]. This is illustrated in ICU patients by reactivation of dormant viruses (CMV or HSV) or infections due to pathogens, including fungi, which are normally pathogenic solely in the immunocompromised host [3][4][5][6]. More specifically, beyond classical risk factors (i.e., prior exposition to antibiotics, central lines, gastrointestinal procedures, total parenteral nutrition in case of candidal bloodstream infections/hematological malignancy, HIV in case of aspergillosis), systemic infections caused by fungal pathogens such as Candida and Aspergillus species have become a prominent cause of disease in severely ill/immunocompromised

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Introduction

Sepsis and related infectious syndromes, including nosocomial infections, represent a major but largely under recognized healthcare problem worldwide, accounting for thousands of deaths every year [1,2]. Despite almost 20 years of anti-inflammatory clinical trials, mortality remains high ranging from 20% for sepsis to over 50% for septic shock [1,2]. The inability of these therapies to mitigate the devastating effects of this condition indicates that the initial hypotheses for sepsis pathophysiology may have been misconstrued or inadequately addressed. In particular, the postulate that death after sepsis is solely due to an overwhelming pro-inflammatory immune response is now considered as inaccurate [1,2].

patients [7][8][9][10]. This may be explained by the incapacity of ICU patients to mount a proper Th-1 response [11][12][13], which constitutes a key step in the host defence against fungal species. In non-ICU patients with invasive aspergillosis, defects in interferon (IFN)-g and TNF-a production have been observed and increased Th-1 responses were associated with improved outcomes [14,15]. Although the mechanistic and molecular bases for ICUacquired immunosuppression are not exhaustively established, several features of the condition have been already described including enhanced leukocyte apoptosis, lymphocyte anergy and deactivated monocyte functions [1,2]. This brief review will focus on immune dysfunctions described so far in ICU patients regarding monocytes and T lymphocytes (as examples for innate and adaptive immune cells) and on their potential use as biomarkers on a routine standardized basis for identification of patients at risk of secondary nosocomial infections and for guidance of putative immunotherapy. Finally, we will more specifically focus on the risk for fungal infections in ICU patients, and on the potential beneficial effects of adjunctive therapy not only to prevent these infections, but also to reinforce immune responses once they are already diagnosed.

T lymphocyte dysfunctions

Functional testing

Lymphocyte anergy in ICU-patients is illustrated by the observation of the loss of delayed-type hypersensitivity reaction to recall skin tests antigens [1,16,17]. This has been described for a long time and is known to be associated with mortality and with the development of secondary infections [1,[16][17][18]. A marked decrease in lymphocyte proliferation in response to antigens (tuberculin, tetanus toxin) or non-specific (phytohemagglutinin, concanavalin A, anti-CD3/anti-CD28 antibodies) stimulations has been described in patients after severe injuries (sepsis, major surgery, severe burn or trauma) [1,18]. Most importantly, it has been observed that the severity of this state of anergy was correlated with poor outcome [1,17], increased occurrence of infectious complications, and subsequent multiorgan failure in patients [17,18]. However, as proliferation tests require a long incubation time (2-3 days for mitogens, 5-7 days for recall antigens), they are not very suitable for clinical decision-making and thus are not performed on a routine basis.

Cell surface marker expression

T lymphocytes have been characterized by the overexpression of inhibitory co-receptors during immunosuppression in ICU. It has recently been demonstrated in trauma patients that anergic T cells presented with increased PD-1, CD47 and CTLA4 expressions that can facilitate preferential triggering of negative signaling pathways during T-cell stimulation [19]. Moreover, this increase in co-repressor receptors appears to be associated with a decrease in the expression of co-activator receptors such as CD28 or CD3, which could also play a role in the development of 20]. However, only fragmentary data are available regarding the correlation of these markers or lymphocyte suppression with mortality/morbidity and the development of nosocomial infections in patients.

Regulatory T cells

A major characteristic of T lymphocyte dysfunctions after severe injury is the increase among patients' circulating lymphocytes of a cell-population with known regulatory properties [17]. CD4  CD25  regulatory T lymphocytes (Treg) have recently been reported as a potent regulatory T cell lineage playing an essential role in the control of both adaptive and innate immune responses [17]. An increase in the percentage of Treg has been described in septic shock patients [21]. Importantly, this increase was observed immediately after the diagnosis of sepsis, but persisted only in non-survivors in association with an augmented CTLA4 expression. A similar increase in Treg percentage has been observed in trauma patients and in mice after polymicrobial septic challenge and stroke [17,22]. We recently observed a strong negative correlation between the increased circulating Treg after septic shock and the decreased lymphocyte proliferation after mitogenic stimulation [23]. This suggests not only that the measurement of Treg percentage may represent a reliable marker for the diagnosis of lymphocyte dysfunctions in patients but also that these cells may play a central role in the development of immunoparalysis after sepsis.

Apoptosis as a mechanism responsible for lymphopenia during sepsis

It is generally agreed that apoptotic cell death represents the major mechanism triggering sepsis-induced lymphocyte anergy/dysfunctions [1,24,25]. After sepsis and severe trauma, this has been shown to be associated with a marked decrease in circulating lymphocyte numbers in correlation with the development of nosocomial infections in these patients [1,17,25]. Pioneering autopsy studies by Hotchkiss et al. disclosed a profound, progressive, apoptosis-induced loss of cells of the adaptive immune system in the spleen, blood and gut-associated lymphoid tissue of adults who had died of sepsis [1,25]

Cell surface marker expression

Several studies in the literature have investigated the expression profile of molecules expressed on the surface of monocytes. Increased attention has been focused on the measurement of HLA-DR (Human Leukocyte Antigen-DR) expression. In ICU patients, a decreased cell-surface expression of HLA-DR has regularly been observed on circulating monocytes, and there is a now general consensus that a diminished mHLA-DR expression is a reliable marker for the development of immunosuppression in critically ill patients [2]. Indeed, the decrease of mHLA-DR expression has been assessed as a predictor for septic complications after trauma, surgery or pancreatitis. In these studies, low levels of mHLA-DR were observed in patients who subsequently developed nosocomial infections [2]. In contrast, in injured patients with uneventful recovery, mHLA-DR rapidly returned to normal values (in general in less than 1 week). Similar results in burn patients and after septic shock also indicate that a low mHLA-DR expression is associated with secondary septic/nosocomial events [35]. Finally, persistent decreased mHLA-DR has been also shown to be predictive of mortality in different groups of critically ill patients [2].

In line, circulating dendritic cells (DCs) also present with decreased mHLA-DR expression and functional impairments in septic shock patients. Moreover, their number is seriously decreased and correlates with poor outcome [36,37].

IL-10 as a soluble mediator responsible for monocyte dysfunctions

Among cytokines released by monocytes and increased after sepsis, IL-10 is the sole cytokine that correlates consistently with mHLA-DR expression [38]. IL-10 production is increased after sepsis and has been shown to predict mortality [1,2]. Given its properties in suppressing the synthesis of numerous pro-inflammatory cytokines [39], this continued release may contribute to the immune dysfunctions observed after septic shock and thus may augment susceptibility to secondary microbial invasion [39]. Gogos et al. showed that IL-10 and IL-10/TNF-a ratios, among a panel of various cytokines (IL-1b, IL-6, sTNF-RI and II), were the most powerful predictors of mortality in patients with severe sepsis [40]. We extended these results by illustrating that IL-10 levels remained higher in non-survivors until 15 days after the onset of septic shock. In particular, high IL-10 concentrations at the beginning of shock were negatively correlated with the nadir of mHLA-DR measurements during the 2 weeks of monitoring [38]. This initial value of IL-10 may reflect the severity of the forthcoming immunoparalysis. Of note, elevated serum IL-10 ill patients without sepsis and healthy volunteers. This induced a profound and persistent lymphopenia associated with poor outcome [26]. Similar results were recently observed by Weber et al. [27]. Finally, Bilbault et al. observed a severe down regulation of the expression of the anti-apoptotic gene Bcl-2 in circulating mononuclear cells from patients with severe sepsis [28]. This was associated with a reduced T-cell count. Most importantly, immediately after the onset of severe sepsis this decrease was higher in non-survivors than in survivors [28,29].

Restoration of lymphocyte functions

Augmenting T cell function and fighting lymphopenia may therefore represent a valuable therapeutic strategy in ICUacquired immunosuppression. Interleukin 7 (IL-7) is an essential cytokine for T lymphocyte development, survival, expansion and maturation in humans [30]. Phase I clinical trials in cancer and HIV-infected patients have shown that T cell expansion can be achieved at doses that are well tolerated [30]. A recent study in mice showed that IL-7 injection was able to promote T cell viability, trafficking and functionality and most importantly improved survival after sepsis [31]. Another therapeutic strategy aimed at blocking apoptosis (caspase-inhibitors, overexpression of Bcl-2, inhibition of Fas/FasL signaling) has demonstrated survival improvement in animal models of sepsis [25]. That said, so far no anti-apoptotic drugs have been sufficiently developed to reach clinical use. An alternative might be provided by HIV protease inhibitors, whose activity is partly mediated through anti-apoptotic effects. Administration of ritonavir improved survival in a murine model of sepsis, even when given after the onset of the disease [32]. As these protease inhibitors are well tolerated in patients, we may expect enticing possibilities in sepsis. In a phase I clinical trial investigating their effects in boosting the immune system, it was shown that nelfinavir monotherapy was able to induce an increase in naïve T-cell numbers in healthy volunteers [33].

Monocyte dysfunctions

Functional testing

Several groups have demonstrated that monocytes from ICU patients usually present with a diminished capacity to release TNF-a, IL-1a, IL-6, IL-12, whereas the release of anti-inflammatory mediators (IL-1Ra, IL-10) is not affected or even slightly increased in response to LPS, other TLR agonists or whole bacteria in vitro [34]. This shows that LPS can still activate monocytes, but that the intracellular signaling pathways may have been turned to favor production of anti-inflammatory molecules, therefore supporting the concept of leukocyte reprogramming [34].

[AQ2]

Restoration of monocyte and dendritic cell functions

Based on decreased mHLA-DR and/or increased circulating IL-10, several innovative immunotherapies may be proposed. AS101, with the capacity to inhibit IL-10, has been demonstrated to increase survival in septic mice [41,42] Given the central role of DCs in both innate and adaptive immune responses, increasing their number and restoring their functions might as well constitute another potential treatment. This is supported by experimental data. For example, septic shock renders mice susceptible to a normally innocuous A. fumigatus lung challenge that, in those circumstances, leads to death [43]. This was associated with an inappropriate cytokine profile of lung DCs, whereas the intrapulmonary transfer of DCs from non septic animals prevented fatal A. fumigatus infection [44]. This mouse model indicates that aspergillosis may occur in septic patients without classical risk factors. Moreover, it has been likely underestimated in ICU patients due to the lack of efficient diagnostic tools [10]. The use of fmslike tyrosine kinase 3 ligand -known to activate and expand DCs -was shown to reverse immunoparalysis in a mice model of endotoxin tolerance [45] and to increase resistance to Pseudomonas aeruginosa opportunistic infections in mice after burns [46].

Several other molecules (IFN-g, G-CSF, GM-CSF) have been used to stimulate monocyte functions with interesting preliminary results (increased mHLA-DR expression, restoration of cytokine production) [1,2]. Several prospective randomized multicentered clinical trials using IFN-g have been conducted in trauma patients [1,2]. However, despite interesting results regarding secondary end-points in some sub-groups of patients (decreased severity of nosocomial infections, decreased mortality in infected patients), they remained inconclusive regarding overall mortality or infection rates [1,47,48]. In a prospective, randomized, placebocontrolled trial, Rosenbloom and colleagues investigated whether GM-CSF treatment improved leukocyte functions and mortality in 40 septic patients [49]. They observed a higher leukocyte count, increased mHLA-DR, and better resolution of infections in the treated group but again, no difference in mortality. Nevertheless, it should be noted that these trials were designed without patient stratification whereas drug efficacy should be assessed only in patients with beforehand-established impairment in monocyte functions. Indeed, in a recent study in 38 selected septic patients based on decreased mHLA-DR expression, Meisel et al. showed that GM-CSF injection was associated with a rapid restoration of this marker's expression and of monocyte capacity to produce TNF-a in response to LPS, as well as with a reduction in ventilation time and hospital/ ICU stay [50]. Another alternative would be to use these cytokines as adjunctive therapy, i.e. not to prevent the development of nosocomial infections, but to reinforce immune responses once they are already diagnosed (see next part).

Fungal infections in ICU patients

Over the past decade, systemic infections caused by fungal pathogens such as Candida and Aspergillus species have become a prominent cause of disease, especially in severely ill or immunocompromised patients. Advances in health care technology and life support systems have increased the risk of nosocomial fungal infection, which are now a major cause of morbidity and mortality in the ICU [51]. Candida albicans is the most frequent cause of candidiasis, although recently a shift has been observed towards non-C. albicans Candida species, especially C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei [52]. There are a limited number of antifungal drugs available for the treatment of systemic mycoses. These include amphotericin B (conventional and liposomal), echinocandins (anidulafungin and caspofungin) and triazoles (fluconazole and voriconazole). The mortality rate associated with candidemia and invasive aspergillosis, independent of death from the underlying disease, is high at around 40%, and tends to increase in patients with unremitting underlying disease [53].

Important risk factors for Candida infection are the use of antibiotics prior to infection, the presence of a central venous or tunneled vascular catheter, surgical procedures, isolation of Candida at another anatomical site, and low neutrophil count [54]. Mechanical ventilation and chronic pulmonary diseases treated with corticosteroids are risk factors for invasive aspergillosis in the ICU [55]. However, in addition to these well known factors, severe fungal infections often develop in critically ill patients who recently suffered from aseptic episodes, and in which sepsis-induced immunoparalysis is an important factor leading to weakened host defenses. In this context, the severity of the disease in ICU patients has been associated with invasive candidiasis, as well as the length of stay in the ICU [8]. The extent of the alteration of the host defense rather than pathogenic properties of the fungus appears to be the most important determinant of the severity of disease [56]. In ICU patients with sepsis, suppression of monocyte and Th1/IFNg responses most likely renders ICU patients more susceptible to severe fungal infections [57,58]. Due to the importance of the defective host defence mechanisms for the increased susceptibility to fungal infections, as well as the persistence of high mortality rates despite the availability of novel classes of antifungal agents such as azoles and echinocandins, it is currently believed that only a combination of antifungals and adjuvant immunotherapy will be able to improve these grim statistics [59].

An accumulating body of evidence suggests that adjunctive immunotherapy with recombinant IFNg is likely to prove beneficial in patients with invasive fungal infections. As presented above, few clinical trials have shown beneficial effects of r-IFNg for the reverse of immunoparalysis in sepsis or trauma patients. Case reports have shown a beneficial effect of r-IFN-g in combination with antifungal drugs in treating a patient with an Aspergillus fumigatus brain abscess [60], and in treating a patient with S. aureus liver abscesses and invasive Candida albicans infection [61]. In addition, in a small study of three patients with disseminated candidiasis, additional IFNg therapy also had beneficial effects [62]. All these observations suggest that IFNg could be beneficial as adjuvant antifungal therapy, but clinical trials are needed to provide definitive proof and suitable recommendations regarding IFNg treatment of invasive fungal infections.

Additional potential strategies using immunostimulatory cytokines recently proposed to be beneficial for the treatment of fungal infections include GM-CSF and G-CSF. In two small studies, Vazquez et al. investigated the use of GM-CSF as an adjunctive treatment for clinically refractory mucosal candidiasis in patients with advanced AIDS. GM-CSF in combination with antifungal therapy appeared to have beneficial effects on clinical improvement and mycological improvement [63,64]. In addition, there have been anecdotal reports in the literature of patients with disseminated candidiasis that were treated with additional GM-CSF and showed a favorable response [62,65]. Although these studies suggest that GM-CSF may be beneficial in the treatment of fungal infections, the number of patients treated with GM-CSF is limited and randomized controlled trials are needed in order to definitively prove a therapeutic effect.

G-CSF is a hematopoietic growth factor that also promotes the proliferation and differentiation of neutrophils. Roilides et al. showed in vitro evidence that incubation of PMNs with G-CSF enhanced antifungal activity in damaging Candida pseudohyphae, probably by modulating cellular membrane receptors [66]. Treatment of mice with G-CSF leads to a significantly reduced mortality and lower fungal outgrowth in experimental disseminated candidiasis [67]. The first randomized placebo controlled trial addressing adjunctive immunotherapy in non-neutropenic patients with disseminated candidiasis, compared fluconazole alone with fluconazole and G-CSF. This phase 2 study indicated that administration of G-CSF is safe and showed a trend towards faster resolution of infection [59].

Thus, in view of the relative deficiency of IFN-g in candidemic patients -especially those with sepsis-induced immunoparalysis -and the beneficial effects of IFN-g on anti-Candida host defense mechanisms, supplementation of r-IFN-g is rational as adjunctive therapy in patients with severe invasive candidasis or candidemia, in addition to treatment with conventional antifungal drugs. Additional potential candidates for immunoadjuvant therapy for fungal infections include GM-CSF and G-CSF. Larger trials specifically designed to assess the beneficial effects of adjuvant immunotherapy for treatment of severe fungal infections are needed in order to ascertain definitively their beneficial effects. However, significant challenges need to be surpassed in order to be able to perform such trials. Firstly, the difficulty in performing large trials in patients with systemic fungal infections is well-known, especially due to the relatively low number of patients that it is possible to recruit. Secondly, the difficulty of clinical endpoints beyond mortality may be addressed by using time-to-negative blood cultures, which may be used in smaller trials. Finally, but not less important, is the lack of support from the pharmaceutical industry, due to the expiration of patents for IFNg and colony stimulating factors. Despite this, one clinical trial assessing the effect of rIFNg on Cryptococcus meningitis is ongoing in South-Africa (trial no. ISRCTN72024361), and a second study on the effect of rIFNg in candidemia is expected to start at the end of the year in the Netherlands (Netea MG, personal communication).

Conclusion

In conclusion, both arms of immunity, innate and adaptive, are severely dysfunctional in patients presenting with ICUacquired immunosuppression. This very likely contributes to the development of nosocomial/fungal infections in these patients as well as to their inability to clear primary infections. Consequently, stimulating the patient's immune system becomes a promising therapeutic strategy. Although we cannot predict which therapies will be efficacious; r-IFNg, GM-CSF and G-CSF appear as promising candidates as they have shown encouraging preliminary results as adjunctive therapy in fungal infections. deserve to be fully and minutely investigated in randomized clinical trials. However, in order not to repeat the mistakes from the past, an absolute prerequisite for the next clinical trials is to systematically assess patients' immune functions to be able to define individualized immunotherapy.

  Give the volume number and page span for Ref. 50?

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	6	[AQ3] Any update yet for Ref. 22?
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  . Accordingly, Le Tulzo et al. observed a marked increase in circulating lymphocyte apoptosis in septic shock patients compared with critically

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© 2010 ISHAM, Medical Mycology, 00, 1-7 ICU-acquired immunosuppression 3

Acknowledgements

G. M. was supported by the Hospices Civils de Lyon. F. V. was supported by FINOVI (Fondation Innovations Infectiologie). M.G.N. was supported by a Vici Grant of the Netherlands Organization for Scientific Research.

Declaration of interest:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.


Stéphane Pitois

Christophe Finot

Lionel Provost

Asymptotic properties of incoherent waves propagating in an all-optical regenerators line

come

Introduction

Over the past years, optical transmission systems enabling very high bit rate operations (160 Gbit/s and beyond) have undoubtedly focused much attention from many research groups.

Alleviating the absence of high-bandwidth electronics at such repetition rates, all-optical techniques have been proposed as a viable alternative solution for signal processing. In particular, all-optical fiber-based regenerators relying on four-wave mixing [1], self-phase modulation (SPM) [2], non-optical loop mirrors optical switch [3] or similariton formation [4] have been reported. In essence, optical regenerators allow discrimination between high power signal and low power noise thanks to the Kerr nonlinearity, whereas dissipation allows useless optical energy to be rejected from the system. Among the various regenerators reported in the literature, the scheme introduced by Mamyshev in Ref. [2] appears as the most robust to simultaneously offer noise suppression in empty bitslots and power equalization on the ones pulses of return-to-zero sequences. Basically, the principle of the Mamyshev's optical Regenerator (MR) relies on the SPM-induced spectral broadening of the degraded signal followed by a subsequent offset spectral filtering. Given the ease of implementation, numerous works have focused their attention on the performance of such regenerators to efficiently restore the quality of corrupted data streams for telecommunication applications [2,[5][6][7].

In this work, we adopt a rather different perspective which allows us to highlight original and fundamental properties of MRs. More precisely, we study the long-term evolution of light by considering the propagation in a line made of a large number of concatenated double-stage MRs, thus focusing our attention on the asymptotic resulting properties of such an arrangement. In a first part, we describe the regenerator line under consideration and report the existence of particular eigenpulses preserving both phase and intensity profiles along the line. In a second part, we take benefit of this remarkable property to generate randomly distributed pulse trains from an incoherent light source. Finally, for some suitable sets of parameters, we demonstrate that the cascaded MRs can support multiple eigenpulses and even limit-cycles.

Principle

The system under consideration (Fig. 1a) is formed by the concatenation of N identical elementary optical blocks. Each elementary block comprises two distinct MR stages. In a first time, light undergoes a large spectral broadening in a highly nonlinear normally-dispersive optical fiber due to the SPM. A detuned optical band-pass Gaussian optical filter (OBPF 1 in Fig. 1a), centered around ω 0 + Ω, is then employed to carve into the spectrum. The shift of the OBPF central frequency washes out from the system a large part of the energy. As a result, only high peak power pulses which have undergone spectral broadening during the propagation can transmit a part of their energy after filtering. The system is thus intrinsically strongly dissipative.

An intermediate optical amplifier compensates for the loss inherent to the described process and boosts the output power to an adequate level for the next MR. The second stage operates in a similar way as the first stage, except that the optical filter (OBPF 2 in Fig. 1a) is now centered around the initial frequency ω 0 and ensures a transparent operation for the whole optical block [8]. Following the proposed implementation, evolution of light along the optical system was modelled by numerically solving the following nonlinear Schrödinger equation :

u u i t u i z u 2 2 2 2 2 γ β = ∂ ∂ + ∂ ∂ ,
parameter and γ the nonlinear coefficient. For the sake of simplicity, we do not incorporate noise from the amplifier and fiber losses in our model.

Existence of eigenpulses

Before studying the propagation of an incoherent wave in the regenerator line, some physical insights could be gained by considering the asymptotic evolution of a single Gaussian pulse in the system. For instance, we consider a chain comprising regenerators of which parameters follow the configuration P1 from Table I. Following the results from Ref [5], this configuration corresponds to a monotonic transfer function exhibiting a constant output power (plateau) over a large input power range. For this configuration and depending on the characteristics of the input pulse (full width at halfmaximum temporal width and peak power), we found that a Gaussian pulse propagating in the regenerator chain can converges towards two well-defined states. The first state corresponds to the absence of light, demonstrating that the propagating pulse is progressively attenuated, and eventually completely suppressed. The second state corresponds to a pulse of determined intensity and phase profiles (see Fig. 1b). More interestingly, we observe that this particular pulse is left unaffected after propagation into an elementary block. Consequently, this stable solution is denoted as eigenpulse by a direct analogy with linear algebra. It is worth noting that the eigenpulse shape and width are mainly imposed by the filter shape and bandwidth [6],

whereas the spectral chirp results from the nonlinear propagation along the optical fibers [5]. The convergence dynamics towards the two possible states is illustrated in Fig. 1c in which basins of attraction corresponding to the system have been plotted as a function of the initial parameters of the input Gaussian pulse. The white-shaded area corresponds to an attraction towards the eigenpulse of the line whereas the dark-shaded area represents the state for which pulse is suppressed. for N =2, (c) N=30.

Generation of random-time pulses sequences

We consider now the evolution of an incoherent wave which slowly varying amplitude is assumed to be a stochastic field of zero mean, obeying Gaussian statistics. The spectral bandwidth of this incoherent source was fixed to 80 GHz, corresponding to a coherence time in the order of 12.5 ps. From an intuitive point of view, we can expect that the propagation of such a multiple peaked structure in the line would asymptotically result in the vanishing of the portion of the signal exhibiting small peaks, whereas convergence towards an eigenpulse can be anticipated for higher peaks. This process is illustrated in Fig. 2 where we have plotted the evolution of an incoherent input signal (Fig. 2a) when few cascaded stages were considered. As expected, and for only N=2 (Fig. 2b), a sequence of picosecond pulses of nearly similar shape is observed. By increasing N, we can furthermore check that each outgoing pulse matches the eigenpulse associated to the line (e.g. N=30, Fig. 2c). It is understandable that the number and the temporal localization of the output pulses are intrinsically seeded by the initial random process associated to the input incoherent signal, and thus they are highly erratic.

At this stage, we would like to emphasize that the operating regime of the optical regenerator, or equivalently the fiber parameters and the offset filter position, have a substantial influence on the asymptotic evolution of the propagating input signal. To illustrate this point, we consider the parameters of the configuration P2 given in Table I. This regenerator line approximately exhibits the same eigenpulse as the configuration P1 but differs by a different power transfer function with a non-monotonic evolution. As a result, the basin of attraction obtained for an incident Gaussian pulse differs significantly from the one obtained with the first configuration (Fig. 3a):

we observe the existence of two distinct narrow areas to be compared with a much larger domain for configuration P1. Consequently for the same input incoherent wave, a reduced number of pulses is generated, as illustrated in Fig. 3c.

Multiple eigenpulses and limit-cycles

For other suitable sets of parameters, we have also observed that the regenerator line reveals more complex behaviors, such as the existence of multiple eigenpulses and limit-cycles. For instance, looking at the evolution for the configuration P3 in Table I, two distinct eigenpulses coexist in the system with respective peak powers of 3.7 W and 4.2 W. When considering an input Gaussian pulse, the convergence towards one of the two invariant solutions or towards a suppressed state is highly dependent on the input pulse characteristics as depicted in the contour plot in Fig. 3b. We observe a multiplicity of basins of attraction for the three possible states forming a complex pattern associated with the formation of the 3.7 W peak power eigenpulse (gray-shaded areas), or 4.2 W peak power eigenpulse (white-shaded areas), or alternatively to the absence of light (black-shaded areas). Similarly when an input incoherent wave is considered, an asymptotical evolution towards a pulse stream exhibiting a random combination of the two eigenpulses is observed (see Fig. 3d).

At this point, we would like to emphasize that the number of attractors, and thus the possibility to observe chaos in the system, depends on the ratios between the different parameters defining the system. To illustrate this property, we consider now the configuration P3 and study the long term evolution of a given incoherent wave for different values of the dispersion parameter D ranging between -1.5 ps/nm/km and 0 ps/nm/km. The peak power values of the multiple eigenpulses that coexist in the system are reported in Fig. 3e as a function of the dispersion parameter D. For high dispersion values, the system converges towards a single well-defined eigenpulse. As the dispersion decreases, many bifurcations occur and the number of eigenpulses significantly increases. Finally, for very small values of D, a large number of attractors coexist and the system presents a chaotic behaviour. Now, we would like to report a particular case for which a propagating pulse can evolve following a limit-cycle trajectory comprising a plurality of eigenpulses. Taking for example the parameters of the configuration P4 from Table I, we demonstrate that the corresponding cascaded MRs can support a limit-cycle made of three eigenpulses respectively denoted Pulse A, B, and C plotted in Fig. 4a-c. After each elementary MRs block, an A-type input pulse is transformed into a B-type, a B-type into a C-type, and eventually a C-type into an A-type, so that the limit-cycle takes the form:

[Pulse A Pulse B Pulse C Pulse A …].
It is worth noting that a longer limit-cycle made of four elements can be also observed for the same configuration.

When an incoherent input wave is injected in this system, the two co-existing limit-cycles promote the apparition of a stream made of multi-level amplitude pulses which is function of the number N. This behaviour is represented in Fig. 4 which shows the evolution of an initial incoherent wave (Fig. 4d) into a sequence of pulses with multiple peak powers (Fig. 4e and4f).

Note the difference in the sequence when an additional elementary block is added.

Conclusion

In this work, we have used a novel approach to highlight original properties of all-optical regenerators based on self-phase modulation and subsequent spectral filtering. It results that such regenerators can be used to generate random sequences of optical pulses from an incoherent wave. This behaviour, which could find applications in the field of random processes generation, is related to the existence of eigenpulses which can propagate unchanged through the regenerator line and act as attractors for the incoming pulses. We anticipate that this last property could be of a particular interest for the design and optimisation of double-stage Mamyshev's optical regenerators for optical telecommunications.

By changing the regenerator parameters, we also report the existence of multiple eigenpulses and limit-cycles. Finally, we expect from these results that Mamyshev's regenerators are likely to act as efficient nonlinear gates in fiber cavity lasers, and thus become a novel method to achieve passive mode-locking.

We would like to acknowledge Dr. P. Petropoulos and Prof. D.J. Richardson (Optoelectronics Research Centre, Southampton, UK) for fruitful discussions.

Fig. 1 .

 1 Fig. 1. (a) Schematic diagram of the regenerator line. OBPF : Optical Band-Pass Filter, EDFA :

Fig. 2 :

 2 Fig. 2: Evolution of an incoherent wave with the parameters of configuration P1. (a) input, (b)

Fig. 3 .

 3 Fig. 3. (a) and (b) Asymptotical states of a Gaussian pulse propagating in the line as a function

Fig. 4 .

 4 Fig. 4. (a), (b), and (c) represent intensity and phase profiles of the pulses constituting the limit-

TABLE I :

 I Parameters of the different configurations

	Configuration	Fiber Length L	Dispersion D	Frequency Offset Ω	EDFA Gain G
	P1	1240 m	-5 ps/nm/km	150 GHz	10.6 dB
	P2	413 m	-5 ps/nm/km	80 GHz	7 dB
	P3	2000 m	-0.8 ps/nm/km	100 GHz	9 dB
	P4	1000 m	-0.5 ps/nm/km	90 GHz	9 dB