Preventive effects of early immunosuppressive treatment on the development of interstitial lung disease in systemic sclerosis.

BACKGROUND: Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc). METHODS: A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression. RESULTS: 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups. CONCLUSION: Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals.

Efficacy of Eating Disorder Focused Family Therapy for Adolescents With Anorexia Nervosa: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review and evaluate the efficacy of eating disorder focused family therapy (FT-ED) in comparison to all other forms of psychotherapy for children and adolescents with anorexia nervosa. A secondary aim is to assess the relative efficacy of different variations of FT-ED (e.g., shorter vs. longer dose, parent-focused). METHODS: A search with relevant terms was systematically conducted on four databases. Twenty-three publications across 18 randomized controlled trials met inclusion criteria. Outcomes of interest included variables related to weight, eating psychopathology, and remission status. Study quality was assessed, and data were extracted by two independent researchers. RESULTS: Adolescents receiving FT-ED gained significantly more weight by the end of treatment in comparison to those receiving individual psychotherapy. FT-ED that was delivered just to parents or to parents and child separately offered preferable weight outcomes and rates of recovery at the end of treatment in comparison to conjoint FT-ED. No other outcomes tested in the meta-analysis were statistically significant at the end of treatment or follow-up. DISCUSSION: Currently available data suggest the use of FT-ED in its conjoint or separated/parent focused format is the best outpatient treatment option for adolescents with anorexia nervosa when immediate weight gain is paramount. The variability of outcome measurement, including the tools used and timepoints chosen, limit comparison among no more than a handful of studies. The field would benefit from the standardization of measurement and reporting guidelines for future clinical trials. TRIAL REGISTRATION: PROSPERO number: CRD42023396263.

OBJETIVO: Revisar y evaluar sistemáticamente la eficacia de la terapia familiar centrada en el trastorno de conducta alimentaria (TF­TCA; FT­ED por sus siglas en inglés) en comparación con todas las demás formas de psicoterapia para niños y adolescentes que padecen anorexia nerviosa. Un objetivo secundario es evaluar la eficacia relativa de diferentes variaciones de la TF­TCA (por ejemplo, dosis más corta vs. más larga, centrada en los padres). MÉTODOS: Se realizó una búsqueda sistemática con términos relevantes en cuatro bases de datos. Veintitrés publicaciones de 18 ensayos controlados aleatorios cumplieron con los criterios de inclusión. Los resultados de interés incluyeron variables relacionadas con el peso, la psicopatología alimentaria y el estado de remisión. La calidad del estudio fue evaluada y los datos fueron extraídos por dos investigadores independientes. RESULTADOS: Los adolescentes que recibieron TF­TCA ganaron significativamente más peso al final del tratamiento en comparación con aquellos que recibieron psicoterapia individual. La TF­TCA que se administró solo a los padres o a padres e hijos por separado ofreció mejores resultados en el peso y tasas de recuperación al final del tratamiento en comparación con la TF­TCA conjunta. Ningún otro resultado probado en el metaanálisis fue estadísticamente significativo al final del tratamiento o durante el seguimiento. DISCUSIÓN: Los datos disponibles actualmente sugieren que el uso de la TF­TCA en su formato conjunto o separado/centrado en los padres es la mejor opción de tratamiento ambulatorio para adolescentes que padecen anorexia nerviosa cuando la ganancia de peso inmediata es primordial. La variabilidad en la medición de los resultados, incluyendo las herramientas utilizadas y los puntos temporales elegidos, limita la comparación entre no más de un puñado de estudios. El campo se beneficiaría de la estandarización de la medición y las directrices de reporte para futuros ensayos clínicos.

[Neuroimmunology of allergic rhinitis part 2 : Interactions of neurons and immune cells and neuroimmunological units]. / Neuroimmunologie der allergischen Rhinitis Teil 2 : Interaktionen von Neuronen und Immunzellen und neuroimmunologische Einheiten.

Allergic rhinitis is an IgE-mediated, type­2 inflammatory disease. neuropeptides are released by neurons and interact with immune cells. Via colocalization, neuroimmune cell units such as nerve-mast cell units, nerve-type 2 innate lymphoid cell (ILC2) units, nerve-eosinophil units, and nerve-basophil units are formed. Markedly elevated tryptase levels were found in nasal lavage fluid and were strongly associated with neuropeptide levels. A close anatomical connection allows bidirectional communication between immune and neuronal cells. Transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin repeat 1 (TRPA1) are critically involved in immunological reactions in the setting of allergic rhinitis. Neuroimmunological communication plays an important role in the inflammatory process, so that allergic rhinitis can no longer be considered a purely immunological disease, but rather a combined neuroimmunological disease.

[Neuroimmunology of allergic rhinitis : Part 1: Cellular and humoral basic principles]. / Neuroimmunologie der allergischen Rhinitis : Teil 1: Zelluläre und humorale Grundlagen.

Allergic rhinitis (AR) is a very common disease with a high prevalence worldwide. It is an IgE-mediated type 2 inflammatory disease following exposure to inhalant allergens. A multitude of different neuropeptides including substance P, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), nerve growth factor (NGF), and neuromedin U (NMU) can be released via peripheral axon or central reflexes, interact with immune cells, and thus contribute to neurogenic inflammation which causes the nasal hyperreactivity (NHR) characteristic of AR. Independent production of neuroendocrine hormones and neuropeptides by immune cells has also been demonstrated. Neuro-immune cell units arise when immune and neuronal cells colocalize, for which typical anatomic regions are, e.g., the mast cell-nerve functional unit. The focus of this review is the elucidation of neuroimmune communication mechanisms in AR.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Mepolizumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Halschirurgie (DGHNOKHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the mucous membranes of the nose and sinuses. Eosinophilic inflammation is described as a common endotype. The anti-IL5 antibody mepolizumab was approved in November 2021 as an add-on therapy to intranasal glucocorticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps when systemic glucocorticosteroids or surgery do not provide adequate disease control. While national and international recommendations exist for the use of mepolizumab in CRSwNP, it has not yet been adequately specified how this therapy is to be monitored, what follow-up documentation is necessary, and when it should be terminated if necessary. METHODS: A literature search was performed to analyze previous data on the treatment of CRSwNP with mepolizumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 10/2022 were considered. RESULTS: Based on the international literature and previous experience by an expert panel, recommendations for follow-up, adherence to therapy intervals and possible therapy breaks, as well as termination of therapy when using mepolizumab for the indication CRSwNP in the German health care system are given on the basis of a documentation sheet. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens up new non-surgical therapeutic approaches with biologics for patients with severe, uncontrolled courses. Here, we provide recommendations for follow-up, adherence to therapy intervals, possible therapy pauses, or discontinuation of therapy when mepolizumab is used as add-on therapy with intranasal glucocorticosteroids to treat adult patients with severe CRSwNP that cannot be adequately controlled with systemic glucocorticosteroids and/or surgical intervention.

Positionspapier: Empfehlungen zur Anwendung von Mepolizumab bei chronischer Rhinosinusitis mit Polyposis nasi (CRSwNP) im deutschen Gesundheitssystem ­ Empfehlungen des Ärzteverbandes Deutscher Allergologen (AeDA) und der AGs Klinische Immunologie, Allergologie und Umweltmedizin und Rhinologie und Rhinochirurgie der Deutschen Gesellschaft für HNO-Heilkunde, Kopf- und Hals-Chirurgie (DGHNO-KHC).

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the paranasal sinus mucosa with eosinophilic inflammation as the most common endotype. The anti-IL5 antibody mepolizumab was approved for the treatment of severe CRSwNP in the EU in November 2021. METHODS: A literature search was performed to analyze the immunology of CRSwNP and determine the available evidence by searching Medline, Pubmed, and the German national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to and including 12/2021 that investigated the effect of mepolizumab in CRSwNP were considered. RESULTS: Based on the international literature and previous experience, recommendations for the use of mepolizumab in CRSwNP in the German health care system are given by an expert panel on the basis of a documentation form. CONCLUSIONS: Understanding about the immunological basis of CRSwNP opens new non-surgical therapeutic approaches with biologics for patients with severe courses. Mepolizumab is approved since November 2021 for add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP who cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

Empfehlungen zur Überprüfung der Wirksamkeit und Verlaufsdokumentation von Dupilumab bei chronischer Rhinosinusitis mit Nasenpolypen (CRSwNP) im deutschen Gesundheitssystem.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifactorial inflammatory disease of the nasal and paranasal mucosa. A Type-2 inflammation is described as the most common endotype. Since October 2019 the anti-IL-4/-IL-13 antibody dupilumab has been approved in Germany as an add-on therapy to intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps, when systemic corticosteroids alone or surgery do not provide adequate disease control. While recommendations for the use of dupilumab in CRSwNP exist at both national and international levels, until now it has not been adequately established, how therapy should be monitored and when it should be discontinued in the German Health Care System. METHODS: A literature search was performed analyzing previous data on the treatment of CRSwNP with dupilumab and to determine the available evidence by searching Medline, Pubmed, the national and international trial and guideline registries and the Cochrane Library. Human studies published in the period up to 05/2022 were included. RESULTS: Based on international literature and previous experience, recommendations are given by an expert panel for follow-up and possible therapy breaks, therapy intervals or termination of therapy when using dupilumab for the indication CRSwNP in the German health care system based on a documentation form. CONCLUSIONS: Understanding the immunological basis of CRSwNP opens new non-surgical therapy approaches with biologics for patients with severe courses. The authors give recommendations for follow-up, possible therapy breaks, therapy intervals and a termination for dupilumab treatment as add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP that cannot be adequately controlled with systemic corticosteroids and/or surgical intervention.

High mobility group box 1 is increased in the sera of psoriatic patients with disease progression.

BACKGROUND: Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease, which appears mostly in skin, but also affects the vascular and metabolic system. The incidence of PV is 2-3% in the general population and there is still no possibility to cure. Trigger factors have been identified to initiate and maintain inflammation in the skin, which is characterized by Th1-, Th17- and Th22- cells. OBJECTIVE: We hypothesize that the damage-associated molecular pattern (DAMP) molecule high mobility group box 1 (HMGB1) plays a role in the pathogenesis of PV. HMGB1 is a DNA-binding protein located in the nucleus, which acquires cytokine-like properties once released from the cell upon necrotic cell death or actively secreted by immune cells in inflammation and cancer. METHODS: We recruited 90 psoriatic patients under and without therapy with mild, intermediate and severe progression of disease, defined by the Psoriasis Area Severity Index. Serum levels of HMGB1 in patients with PV were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results show an increased level of HMGB1 in the sera of patients with PV in comparison to healthy donors. Furthermore, our analyses reveal that HMGB1 levels are significantly increased with disease progression and are downregulated after standard therapies for PV have been conducted. CONCLUSION: Our data provide insights into a possible role of HMGB1 for inflammation in PV.

[Hemolytic kidney failure and transient ischemic attack in a 32-year-old female]. / Hämolytisches Nierenversagen mit transitorisch ischämischer Attacke bei einer 32-Jährigen.

We report on the case of a 32-year-old female patient who initially presented with oliguric acute renal failure, hemolytic anemia with moderate thrombocytopenia and subsequently developed a transient ischemic attack in the cerebellum. The kidney biopsy revealed clinically suspected atypical hemolytic-uremic syndrome (aHUS), which was confirmed by intraglomerular thrombotic microangiopathy (TMA). Treatment with plasmapheresis and sustained administration of the C5 inhibitor eculizumab resulted in hematological remission but without improvement of kidney function. Further etiological investigations led to reduced plasma levels of inhibitory complement factor I on the basis of a heterozygous CFI mutation. In patients with aHUS molecular genetic investigations are indicated in order to determine the underlying cause, to regulate the therapeutic regimen and to allow prognostic statements with respect to a potential kidney transplantation.

Syndromic ciliopathies: From single gene to multi gene analysis by SNP arrays and next generation sequencing.

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS.

[The primary use of pectoralis myofascial flap in salvage laryngectomy]. / Die primäre Verwendung des myofaszialen M. pectoralis-major-Lappens bei der Salvage-Laryngektomie.

BACKGROUND: The salvage laryngectomy (SLE) is very often the only curative option in recurrent laryngeal or hypopharyngeal carcinomas. But the SLE is associated with an increased risk of complications such as the formation of salivary fistulas. To reduce the rate of fistulas a simultaneous elevation of the myofascial pectoralis major flap (PMML) is described. The aim of this study was to compare the SLE with and without the use of the PMML for prophylaxis of salivary fistulas. PATIENTS AND METHOD: 9 patients were included, suffering from a T4a larynx or hypopharynx carcinoma recurrence after RCT in the years 2012 and 2013 and subsequently treated by a SLE. An additional elevation of PMML was indicated due to the following criteria: end of RCT less than one year ago, tumor localization outside the glottis, infiltration of thyroid cartilage and prelaryngeal muscles. After PMML elevation the flap was sewed onto a primary closed pharynx. RESULTS: 6 out of 9 patients (2/3) received an additional covering of the pharynx by the PMML during SLE. In no case a postoperative salivary fistula was seen. In the remaining 3 patients (1/3) the pharynx was primarily closed without an additional covering by the PMML. In this group of patients one postoperative salivary fistula was seen. CONCLUSION: Due to the simultaneous application of the PMML in the context of SLE the rate of postoperative salivary fistula could be effectively reduced in our own patients. The PMML is suitable due to its safe elevation technique, the missing secondary thoracal cutaneous defect, and a good modelling possibility in the recipient area.

Branchio-otic syndrome caused by a genomic rearrangement: clinical findings and molecular cytogenetic studies in a patient with a pericentric inversion of chromosome 8.

Branchio-oto-renal (BOR) syndrome is an autosomal dominantly inherited developmental disorder, which is characterized by anomalies of the ears, the branchial arches and the kidneys. It is caused by mutations in the genes EYA1,SIX1 and SIX5. Genomic rearrangements of chromosome 8 affecting the EYA1 gene have also been described. Owing to this fact, methods for the identification of abnormal copy numbers such as multiplex ligation-dependent probe amplification (MLPA) have been introduced as routine laboratory techniques for molecular diagnostics of BOR syndrome. The advantages of these techniques are clear compared to standard cytogenetic and array approaches as well as Southern blot. MLPA detects deletions or duplications of a part or the entire gene of interest, but not balanced structural aberrations such as inversions and translocations. Consequently, disruption of a gene by a genomic rearrangement may escape detection by a molecular genetic analysis, although this gene interruption results in haploinsufficiency and, therefore, causes the disease. In a patient with clinical features of BOR syndrome, such as hearing loss, preauricular fistulas and facial dysmorphisms, but no renal anomalies, neither sequencing of the 3 genes linked to BOR syndrome nor array comparative genomic hybridization and MLPA were able to uncover a causative mutation. By routine cytogenetic analysis, we finally identified a pericentric inversion of chromosome 8 in the affected female. High-resolution multicolor banding confirmed the chromosome 8 inversion and narrowed down the karyotype to 46,XX,inv(8)(p22q13). By applying fluorescence in situ hybridization, we narrowed down both breakpoints on chromosome 8 and found the EYA1 gene in q13.3 to be directly disrupted. We conclude that standard karyotyping should not be neglected in the genetic diagnostics of BOR syndrome or other Mendelian disorders, particularly when molecular testing failed to detect any causative alteration in patients with a convincing phenotype.

[Regulatory T cells and NK cells in cancer patients]. / Regulatorische T-Zellen und NK-Zellen bei Krebspatienten.

NK cells represent the cells of the immune system most effective for eradication of infected or neoplastic cells. Regulatory T cells and the two main subgroups thereof-the naturally occurring nTregs and the tumor-associated induced Tregs (iTregs)-play an important role in the antitumor immune response in cancer patients. The current study explores the intercellular interactions of these groups of cells in tumor patients, particularly in head and neck cancer. Critical interactions between these cells and the cancer cells could be observed in extensive experimental analyses. Firstly, we generated tumor-associated iTregs in a specific human culture. Subsequently, various phenotypic and functional relationships between these cells, nTregs, NK cells and tumor cells were analyzed in an autologous system. Although the activity of naive NK cells was enhanced by iTregs in the presence of tumor cells, the cytotoxic function of NK cells activated by interleukin-2 was markedly inhibited by iTregs and nTregs. Our group was able to document new insights into the complex regulation of human NK cells and regulatory T cells in the tumor microenvironment. These new insights may be of relevance for an improved understanding of the antitumor immune response and the development of immunotherapeutic strategies.

[Treatment of recurrent epistaxis by artery ligation: up to date or old fashioned?]. / Behandlung rezidivierender Epistaxis durch Gefäßligatur: zeitgerecht oder überholt?

UNLABELLED: Treatment of Recurrent Epistaxis by Artery Ligation: Up to Date or Old Fashioned? BACKGROUND: Despite the ongoing development in the field of endoscopic treatment techniques, recurrent epistaxis remains a challenge for otolaryngologists. The aim of the present study was to compare our own results of various interventions for the treatment of recurrent epistaxis. MATERIALS AND METHODS: From 2007 to 2013 we performed surgical treatment of recurrent epistaxis under general anaesthesia in 148 cases. While the majority of causes were idiopathic (n=98), epistaxis also occurred postoperatively (n=30), post-traumatically (n=7) or as a result of M. Osler (n=12). In 141/148 cases the treatment was performed by mono- or bipolar coagulation in the area of the bleeding source - this required an ethmoidectomy in 17 cases. In 19 cases the intervention was combined with a septoplasty. In 4 patients with recurrent bleeding of unknown origin, where electrocoagulation under general anaesthesia failed, we performed a clipping of the ethmoid- and/or the maxillary arteries in the pterygopalatine fossa. Following this intervention no further bleeding episodes occured. In further 3 patients, neuroradiological embolization was successfully performed. CONCLUSION: If conservative measures fail in the treatment of epistaxis, surgical treatment by electrocoagulation of the bleeding site under general anaesthesia is an effective intervention in 95% of cases. However for the remaining 5% where these measures have been proven to be ineffective, clipping of the ipsilateral anterior and posterior ethmoid- and/or the maxillar artery provides a treatment option being equally efficient as neuroradiological interventions.

Niobium pentoxide as a new filler for methacrylate-based root canal sealers.

AIM: To evaluate the influence of several niobium pentoxide (Nb(2) O(5) ) concentrations on the radio-opacity, flow, film thickness, microhardness and degree of conversion of an experimental root canal sealer. METHODOLOGY: An experimental dual-cured root canal sealer was produced with a methacrylate-based comonomer blend. Nb(2) O(5) was added at four different concentrations: 0, 80, 100 and 120 wt%. Radio-opacity was evaluated according to ISO 6876 using a digital system (n = 5). Flow and film thickness were determined in accordance with ISO 6876 (n = 3). Microhardness was evaluated with 50 g for 15 s (n = 5). Degree of conversion was evaluated with FTIR immediately after photocuring and after 1, 7 and 14 days. The data were analysed using anova and Tukey's test. The degree of conversion over time was evaluated using RM-anova (α = 0.05). RESULTS: The groups with 80 wt% and 100 wt% of filler showed no significant difference in radio-opacity from that of equivalent 2 mmAl (P > 0.05). The addition of 120 wt% resulted in radio-opacity values higher than 2 mmAl (P < 0.05). The flow was not significantly different amongst the different groups (P > 0.05). All groups had a film thickness of <50 µm (ISO 6876). All groups with Nb(2) O(5) were associated with higher values of microhardness than the control group. The group with 0 wt% was associated with a higher degree of conversion at all times. All groups except those with 80 wt% had higher values for degree of conversion after 14 days than immediately after photocuring. CONCLUSION: The addition of Nb(2) O(5) increases radio-opacity and microhardness; this material may be a promising filler for the production of a new endodontic sealer.