[Chronic rhinosinusitis with nasal polyposis : A retrospective analysis of therapeutic approaches in 463 patients]. / Chronische Rhinosinusitis mit Polyposis nasi : Retrospektive Analyse des therapeutischen Vorgehens bei 463 Patienten.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease, the treatment of which has undergone significant changes in recent years. In addition to surgical approaches, topical and systemic steroids, and adaptive acetylsalicylic acid (ASA) desensitization, three specific antibodies have complemented the therapeutic portfolio since 2019. METHODS: A retrospective evaluation of all patients who presented as outpatients for the first time due to CRSwNP in 2007 and 2008 (collective A) and 2017 and 2018 (collective B) was performed, up to and including June 2023. RESULTS: The clinical courses of 463 patients (mean age 49.1 years, range 5-82 years; 65.9% male) were included in the analysis. Conservative treatment with nasal corticosteroids started before initial presentation was more frequent in collective B (collective A 43.9% vs. collective B 72.2%). In 278 of the 463 patients (60%; A: 62%, B: 58%), at least one operation on the nasal sinuses had been performed after initial presentation; in 101 of these patients (36.3%) recurrent polyposis (within mean follow-up of 2.4 years) required further treatment. The indication for ASA provocation/desensitization was applied less frequently in collective B, also due to a high discontinuation rate (at least 38%) of the maintenance therapy. Of the total cohort, 16 patients (3.5%; A: n = 8, B: n = 8) were meanwhile switched to antibody therapy at recurrence. CONCLUSION: A step-by-step guideline-orientated approach is recommended in the treatment of CRSwNP. Systemic antibodies as an add-on to nasal corticosteroids are a relatively new therapeutic option for treatment-refractory CRSwNP, which reduces the indication for ASA desensitization, which is associated with a relatively high incidence of side effects and poor compliance.

[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.

Chemical Responses of Nicotiana tabacum (Solanaceae) Induced by Vibrational Signals of a Generalist Herbivore.

Plants are able to sense their environment and respond appropriately to different stimuli. Vibrational signals (VS) are one of the most widespread yet understudied ways of communication between organisms. Recent research into the perception of VS by plants showed that they are ecologically meaningful signals involved in different interactions of plants with biotic and abiotic agents. We studied changes in the concentration of alkaloids in tobacco plants induced by VS produced by Phthorimaea operculella (Lepidoptera: Gelechiidae), a generalist caterpillar that naturally feeds on the plant. We measured the concentration of nicotine, nornicotine, anabasine and anatabine in four treatments applied to 11-weeks old tobacco plant: a) Co = undamaged plants, b) Eq = Playback equipment attached to the plant without VS, c) Ca = Plants attacked by P. operculella herbivory and d) Pl = playback of VS of P. operculella feeding on tobacco. We found that nicotine, the most abundant alkaloid, increased more than 2.6 times in the Ca and Pl treatments as compared with the Co and Eq treatments, which were similar between them. Nornicotine, anabasine and anatabine were mutually correlated and showed similar concentration patterns, being higher in the Eq treatment. Results are discussed in terms of the adaptive significance of plant responses to ecologically important VS stimuli.

In situ analysis of interleukin-6 expression at different sites of zygapophyseal joints from patients with ankylosing spondylitis in comparison to controls.

OBJECTIVES: Analysis of interleukin (IL)-6 serum levels in patients with ankylosing spondylitis (AS) has indicated that IL-6 might be a pro-inflammatory cytokine involved in AS. However, two placebo-controlled trials with monoclonal antibodies directed against the IL-6 receptor have failed to demonstrate the efficacy of the monoclonal humanized anti-human IL-6 receptor antibody over placebo for the treatment of symptoms of AS. In this study we conducted an in situ analysis of IL-6 expression at different sites of inflammation in zygapophyseal joints of patients with AS in comparison to osteoarthritis autopsy controls (CO). METHOD: Our immunohistochemical analysis involved 14 patients with AS, 12 autopsy controls (CO), and 11 patients with osteoarthritis (OA). Immunohistochemistry was performed to detect IL-6+ cells at five different sites: within subchondral bone marrow, fibrous tissue replacing subchondral bone marrow, hyaline cartilage, and the subchondral bone plate, and at entheseal sites. RESULTS: Apart from changes in subchondral bone marrow, no significant differences were observed at the sites analysed when comparing AS patients and controls. A significantly lower frequency of IL-6+ cells was evident in AS patients compared to controls (p = 0.0043). In addition, AS patients tended to have even lower percentages of IL-6+ cells than controls at subchondral bone plates and entheseal sites. A significantly lower number of IL-6 expressing cells was also seen within the fibrous tissue of AS compared to OA patients (p = 0.0237). CONCLUSIONS: This in situ analysis confirms that IL-6 is not a key player in the pathogenesis of inflammatory processes in spondyloarthritides (SpA). The relevance of pro-inflammatory agents in axial SpA might be studied better in situ in bony specimens at the primary site of inflammation.

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.

[Rituximab for treatment of Felty's syndrome]. / Rituximab zur Therapie des Felty-Syndroms.

Felty's syndrome is a rare variant of severe seropositive rheumatoid arthritis with neutropenia and splenomegaly. It is difficult to treat and associated with a poor prognosis due to the substantial risk of infections. This article presents the case of a patient with refractory disease who responded to rituximab with permanent normalization of neutrophil counts. Repeated infusions were necessary to induce and maintain remission.

Determining excitation-energy transfer times and mechanisms from stochastic time-dependent density functional theory.

We developed an approach for calculating excitation-energy transfer times in supermolecular arrangements based on stochastic time-dependent density functional theory (STDDFT). The combination of real-time propagation and the stochastic Schrödinger equation with a Kohn-Sham Hamiltonian allows for simulating how an excitation spreads through an assembly of molecular systems. The influence that approximations, such as the dipole-dipole coupling approximation of Förster theory, have on energy-transfer times can be checked explicitly. As a first application of our approach we investigate a light-harvesting-inspired model ring system, calculating the time it takes for an excitation to travel from one side of the ring to the opposite side under ideal and perturbed conditions. Among other things we find that completely removing a molecule from the ring may inhibit energy transfer less than having an energetically detuned molecule in the ring. In addition, Förster's dipole coupling approximation may noticeably overestimate excitation-energy transfer efficiency.

[Biomarkers in rheumatology. Biomarkers and imaging for the diagnosis and stratification of rheumatoid arthritis and spondylarthritis in the ArthroMark network funded by the Federal Ministry of Education and Research]. / Biomarker in der Rheumatologie. Biomarker und Bildgebung zur Diagnose und Stratifizierung der rheumatoiden Arthritis und Spondylarthritis im BMBF-Verbund ArthroMark.

The introduction of biologics has continuously increased the demand for biomarkers for early diagnosis and therapeutic stratification. ArthroMark, a research network funded by the Federal Ministry of Education and Research, aims to establish such biomarkers for rheumatoid arthritis and spondyloarthritides. Biobanks and previous work on genotyping, gene expression and autoreactivity profiling build the basis. Bioinformatic networks will help to harmonize the investigations and a clinical study with modern imaging techniques to characterize the functional relevance of the new biomarkers as effectively as possible. To validate the markers for diagnostic application the network aims to expand gradually.

Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial.

OBJECTIVE: Histologic studies have shown B cell clusters in the subchondral bone marrow of the spine of patients with ankylosing spondylitis (AS). An immunotherapy targeting B cells in AS is therefore of interest. We undertook this study to examine the efficacy and safety of rituximab in patients with AS refractory to nonsteroidal antiinflammatory drugs in whom previous treatment with tumor necrosis factor alpha (TNFalpha) blockers either had not been tried or had failed. METHODS: In this phase II clinical trial, 1,000 mg rituximab was administered intravenously at baseline and at week 2 in 20 patients with active AS. Ten of these patients had never received TNF blockers, and treatment with TNF blockers had failed in the other 10 patients. The primary end point was a 20% improvement in disease activity at week 24 according to the criteria of the Assessment of SpondyloArthritis international Society (an ASAS20 response). RESULTS: Seventy-five percent of the patients were male, 90% were HLA-B27 positive, their mean age was 39.7 years, and their mean disease duration was 16.8 years. Patients had active disease, defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score >or=4. While there was no clear response at week 24 in the group in whom TNF blockers had failed (30% had achieved an ASAS20 response, 10% had achieved an ASAS40 response, none had achieved partial remission according to the ASAS criteria, and none had achieved 50% improvement on the BASDAI [a BASDAI50 response] beyond an expected placebo response), we observed a good improvement in the TNF blocker-naive group at week 24 (50% had achieved an ASAS20 response, 40% had achieved an ASAS40 response, 30% had achieved partial remission according to the ASAS criteria, and 50% had achieved a BASDAI50 response). CONCLUSION: Although rituximab does not seem to be effective in patients with AS that does not respond to TNF blockers, it had significant efficacy in TNF blocker-naive patients. Therefore, further controlled trials with B cell-directed therapies should be performed in TNF blocker-naive AS patients in the future.

Rheumatoid arthritis and ankylosing spondylitis - pathology of acute inflammation.

Histomorphological analysis of inflammatory lesions in rheumatoid arthritis (RA) and ankylosing spondylitis (AS) display similarities but also major differences. Ankylosing spondylitis is characterised by two key pathological findings: sacroiliac joint and spinal inflammation and new bone formation with the possible consequence of bone fusion, usually in the axial skeleton. In AS the primary site of inflammation is located at the enthesis or subchondral bone marrow with bone marrow oedema, lymphocytic infiltrates, increased osteoclast density and increased microvessel density are typical findings in acute inflammation. In RA joint inflammation has its origin in the synovial membrane of peripheral joints. Osteitis in the subchondral bone marrow reveals similar findings compared to AS and it is suggested to occur secondary to inflammation in the synovial membrane. Structural damage defines the outcome in both diseases. However, in AS it is defined by new bone formation and in RA by the destruction of cortical bone.

[Immunopathology of ankylosing spondylitis and other spondyloarthritides]. / Immunpathologie bei der ankylosierenden Spondylitis und anderen Spondyloarthritiden.

Histomorphological analysis shows at least two different patterns in patients with ankylosing spondylitis. Bone marrow edema, lymphocytic infiltrates, increased osteoclast density and increased microvessel density are typical findings in acute inflammation. In areas of new bone formation newly formed trabecular bone shows formation of fibrous tissue in the bone marrow with new cartilage formation and persistently high microvessel density. Morphological changes reminiscent of endochondral ossification can also be observed. Compared to peripheral joints, such as the knee, synovitis is not a predominant finding in the spine, the sacroiliac joints and the hip. Enthesitis is characterised by lymphocytic infiltrates around fibrous cartilage followed by subsequent ankylosis. The molecular mechanisms which promote the transition from inflammation to new bone formation in patients with ankylosing spondylitis are not well understood.

Massive creatine kinase elevations with quetiapine: report of two cases.

Massive elevations of serum creatine kinase (CK) can occur in a significant number of patients treated with neuroleptics in the absence of neuroleptic malignant syndrome (NMS). We report two cases of CK-elevations associated with quetiapine treatment, which disappeared after drug discontinuation. To our knowledge, case number one is the first case of quetiapine-induced CK elevation in a neuroleptic-naïve patient. We thus suggest CK assessment when myalgia occurs with neuroleptic treatment.

Measuring the kernel of time-dependent density functional theory with x-ray absorption spectroscopy of transition metals.

The 2p-3d core-hole interaction in the L2.3 absorption spectra of the transition metals is treated within time-dependent density functional theory. A simple three-level model explains the origin of the strong deviations from the one-particle branching ratio and yields matrix elements of the unknown exchange-correlation kernel directly from experiment.

Analysis of the CD8+ T cell response to the G1 domain of aggrecan in ankylosing spondylitis.

BACKGROUND: CD4+ T cell responses to the G1 domain of aggrecan in patients with ankylosing spondylitis (AS) were recently reported. Whether such an immune response can be seen in the CD8+ subpopulation has not yet been determined. OBJECTIVE: To determine if HLA-B27 restricted G1-specific CD8+ T cells are present in AS and to analyse immunodominant CD8+ T cell epitopes. METHODS: Peripheral blood mononuclear cells of 45 patients with AS were stimulated with overlapping 18-mer peptides covering the whole G1 protein. Results were compared with those for patients with rheumatoid arthritis (RA) and healthy controls. For epitope analysis, G1-specific interferon gamma positive (IFNgamma+) T cells were isolated by magnetic activated cell sorting. After in vitro expansion, CD8+ T cells were restimulated with 14 subpools of G1 peptides. T cells responding to G1 peptide subpools were quantified by flow cytometry according to IFNgamma secretion. Predicted peptides were subsequently confirmed by stimulation with single peptides. RESULTS: G1-specific CD8+ T cell responses were found in 29/45 (64%) patients with AS, 18/35 (51%) patients with RA, but not in healthy controls. Five CD8+ T cell epitopes were identified as immunodominant in five patients. However, the T cell response was not HLA-B27 restricted. Nonamer peptides with an HLA-B27 binding motif did not induce a T cell response. CONCLUSION: A G1 peptide-specific CD8+ T cell response is present in AS but also in patients with RA. It does not seem to be HLA-B27 restricted. Whether such a response has a role in the pathogenesis of AS needs clarification.

Excitations in time-dependent density-functional theory.

An approximate solution to the time-dependent density-functional theory response equations for finite systems is developed, yielding corrections to the single-pole approximation. These explain why allowed Kohn-Sham transition frequencies and oscillator strengths are usually good approximations to the true values, and why sometimes they are not. The approximation yields simple expressions for Görling-Levy perturbation theory results, and a method for estimating expectation values of the unknown exchange-correlation kernel.

Identification of HLA-B27-restricted peptides from the Chlamydia trachomatis proteome with possible relevance to HLA-B27-associated diseases.

The association of HLA-B27 with ankylosing spondylitis and reactive arthritis is the strongest one known between an MHC class I Ag and a disease. We have searched the proteome of the bacterium Chlamydia trachomatis for HLA-B27 binding peptides that are stimulatory for CD8(+) cells both in a model of HLA-B27 transgenic mice and in patients. This was done by combining two biomathematical computer programs, the first of which predicts HLA-B27 peptide binding epitopes, and the second the probability of HLA-B27 peptide generation by the proteasome system. After preselection, immunodominant peptides were identified by Ag-specific flow cytometry. Using this approach we have identified for the first time nine peptides derived from different C. trachomatis proteins that are stimulatory for CD8(+) T cells. Eight of these nine murine-derived peptides were recognized by cytotoxic T cells. The same strategy was used to identify B27-restricted chlamydial peptides in three patients with reactive arthritis. Eleven peptides were found to be stimulatory for patient-derived CD8(+) T cells, of which eight overlapped those found in mice. Additionally, we applied the tetramer technology, showing that a B27/chlamydial peptide containing one of the chlamydial peptides stained CD8(+) T cells in patients with Chlamydia-induced arthritis. This comprehensive approach offers the possibility of clarifying the pathogenesis of B27-associated diseases.

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.

The adapter protein apoptotic protease-activating factor-1 (Apaf-1) is proteolytically processed during apoptosis.

Apoptotic protease-activating factor-1 (Apaf-1), a key regulator of the mitochondrial apoptosis pathway, consists of three functional regions: (i) an N-terminal caspase recruitment domain (CARD) that can bind to procaspase-9, (ii) a CED-4-like region enabling self-oligomerization, and (iii) a regulatory C terminus with WD-40 repeats masking the CARD and CED-4 region. During apoptosis, cytochrome c and dATP can relieve the inhibitory action of the WD-40 repeats and thus enable the oligomerization of Apaf-1 and the subsequent recruitment and activation of procaspase-9. Here, we report that different apoptotic stimuli induced the caspase-mediated cleavage of Apaf-1 into an 84-kDa fragment. The same Apaf-1 fragment was obtained in vitro by incubation of cell lysates with either cytochrome c/dATP or caspase-3 but not with caspase-6 or caspase-8. Apaf-1 was cleaved at the N terminus, leading to the removal of its CARD H1 helix. An additional cleavage site was located within the WD-40 repeats and enabled the oligomerization of p84 into a approximately 440-kDa Apaf-1 multimer even in the absence of cytochrome c. Due to the partial loss of its CARD, the p84 multimer was devoid of caspase-9 or other caspase activity. Thus, our data indicate that Apaf-1 cleavage causes the release of caspases from the apoptosome in the course of apoptosis.