[Chronic rhinosinusitis with nasal polyps-extension of dupilumab treatment intervals]. / Chronische Rhinosinusitis mit nasalen Polypen ­ Verlängerung der Dupilumab-Therapieintervalle.

BACKGROUND: In patients with severe, uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP), dupilumab 300 mg every 2 weeks can completely resolve nasal polys, sinus disease, and symptoms. In this case, patients ask for de-escalation. Although trials have demonstrated recurrence after stopping the biologic at 24 weeks, reducing the dose of dupilumab to once every 4 weeks did not result in deterioration of control. An extension of the treatment intervals would, however, diverge from the approval text, and is currently not recommended. METHODS: The course of 29 patients with severe CRSwNP, type­2 inflammation-associated comorbidities, and an indication for biologic was retrospectively analyzed. After resolution of CRSwNP and symptoms under biweekly dupilumab 300 mg, the dupilumab interval had been prolonged individually, initially up to 4 weeks, thereafter up to 6 weeks, if applicable. Control was assessed via quality of life (22-item sinonasal outcome test, SNOT-22), nasal polyp score, and smell identification test (Sniffin' Sticks; Burghart Messtechnik, Holm, Germany). RESULTS: All patients showed an excellent improvement within the first 3 months. The dupilumab application interval was extended to 4 weeks after 7-31 months (median 13 months) and to 6 weeks (n = 9) after 17-35 months (median 23 months). No recurrent polyps or symptoms were subsequently observed. CONCLUSION: In case of maximal regression of polyps and discomfort, extension of dupilumab injection intervals to 4 and potentially 6 weeks is possible without clinical worsening. Further studies on de-escalation or termination of biologic treatment when CRSwNP control is achieved are essential.

Plants respond to leaf vibrations caused by insect herbivore chewing.

Plant germination and growth can be influenced by sound, but the ecological significance of these responses is unclear. We asked whether acoustic energy generated by the feeding of insect herbivores was detected by plants. We report that the vibrations caused by insect feeding can elicit chemical defenses. Arabidopsis thaliana (L.) rosettes pre-treated with the vibrations caused by caterpillar feeding had higher levels of glucosinolate and anthocyanin defenses when subsequently fed upon by Pieris rapae (L.) caterpillars than did untreated plants. The plants also discriminated between the vibrations caused by chewing and those caused by wind or insect song. Plants thus respond to herbivore-generated vibrations in a selective and ecologically meaningful way. A vibration signaling pathway would complement the known signaling pathways that rely on volatile, electrical, or phloem-borne signals. We suggest that vibration may represent a new long distance signaling mechanism in plant-insect interactions that contributes to systemic induction of chemical defenses.

Limitations of Folin assays of foliar phenolics in ecological studies.

We examined the response of the widely used Folin-Denis assay to purified tannins from 16 woody plant species and to three commercial polyphenol preparations often used as standards. The reagent's response to these chemical mixtures differed significantly among sources (tree species, commercial preparations) and sampling dates, even though the mixtures contained the same total dry weight of tannins. Response to commercial standards usually did not resemble response to actual plant tannin and produced estimates that differed from actual concentrations by as much as twofold. Species-based and seasonal differences in polyphenol composition are evidently responsible for these variable results. Reagents that depend on redox reactions, such as the Folin-Denis, do not produce reliable absolute or relative quantification of phenolics when different species or samples from different dates are compared, and use of commercial standards does not resolve this problem.

Gut physicochemistry of grassland grasshoppers.

We examined the pH and Eh of the digestive tract of 23 species of mixed-grass prairie grasshoppers, and asked whether these traits were associated with the species breadth and forb composition of their diets. We report that the gut lumen of all grasshoppers was oxidizing and ranged from slightly acid to neutral depending on the gut region and species. Although gut physicochemical conditions differed among species, the differences were of small magnitude. Conditions were fairly uniform along the digestive tract, which suggests little or no regulation of pH or Eh. Gut conditions were independent of diet breadth and the percentage of forbs in the diet. These results suggest that physicochemical conditions of grasshopper guts are not highly regulated and are not influenced by their most recent meal or by broad scale patterns of host-plant use.

Impact of dietary allelochemicals on gypsy moth (Lymantria dispar) caterpillars: importance of midgut alkalinity.

Midgut pH of gypsy moth larvae was depressed artificially with buffered diet to examine the impact of alkalinity on the caterpillars' ability to tolerate a dietary polyphenol and a quinone. A 2x3 factorial design was used, with 2 levels of succinate buffer and 3 dietary amendments (tannic acid, juglone, or control). Development was monitored during the third and fourth instars, with consumption, food passage rates, midgut pH, and midgut redox potential (Eh) measured in the fourth instar. Diet buffering successfully depressed midgut pH to hypothetically suboptimal acidic levels without reductions in survivorship, but it did reduce larval growth and impede development. Buffering dramatically reduced survivorship of fourth instar larvae eating diets containing tannic acid or juglone. Growth increased on unbuffered diet amended with tannic acid, but not with juglone. Caterpillars passed food through the gut more slowly when feeding on buffered tannic acid diet or on unbuffered juglone diet. These results indicate that maintenance of midgut alkalinity is critical to tolerance of dietary tannic acid and juglone, and that these allelochemicals have very different activities in the caterpillar gut.

Phenolics in ecological interactions: The importance of oxidation.

The ecological activities of plant phenolics are diverse and highly variable. Although some variation is attributable to differences in concentration, structure, and evolutionary history of association with target organisms, much of it is unexplained, making it difficult to predict when and where phenolics will be active. I suggest that our understanding is limited by a failure to appreciate the importance of oxidative activation and the conditions that influence it. I summarize examples of oxidative activation of phenolics in ecological interactions, and argue that physicochemical conditions of the environment that control phenolic oxidation generate variation in ecological activity. Finally, I suggest that measurements of oxidative conditions can improve our predictions of phenolic activity and that experiments must be designed with conditions appropriate to the biochemical mode of phenolic action.

Gut redox conditions in herbivorous lepidopteran larvae.

Large interspecific differences in redox potential exist among herbivorous lepidopteran larvae. Reducing conditions occur in the midguts ofManduca sexta (Sphingidae) andPolia latex (Noctuidae), whereas oxidizing conditions prevail in the midguts ofLymantria dispar (Lymantriidae),Danaus plexippus (Danaidae), andPapilio glaucus (Papilionidae). The epithelium of the posterior midgut ofM. sexta fed a diet containing bismuth subnitrate accumulates bismuth sulfide, suggesting that sulfide might be one of the reducing agents responsible for the maintenance of reducing conditions in this species. We propose that the effects of plant allelochemicals in insect herbivores will be strongly affected by gut redox conditions and that the regulation of gut redox conditions is an important adaptation of insect herbivores to the chemical defenses of plants. The redox state of the gut is yet another insect trait that must be included in the analysis of plant-insect interactions.