Die Bedeutung der STAT3-Blockade durch Tyrphostin AG 490 im neonatalen Tiermodell der obstruktiven Uropathie

Angeborene obstruktive Uropathien lösen eine ausgeprägte zytokinvermittelte Entzündungsreaktion in der Niere aus. Pro-inflammatorische Signalwege sind wesentlich an der Aufrechterhaltung dieser Entzündung im Sinne eines Circulus vitiosus beteiligt. Dies führt zu tubulärer Apoptose, tubulärer Atrophie und interstitieller Fibrose. Unter anderem ist daran der „Signal Transducer and Activator of Transkription“ (STAT3) als pro-inflamma-torischer und pro-fibrotischer Transkriptionsfaktor beteiligt. Deshalb untersuchte die vorliegende Arbeit die Bedeutung einer STAT3-Blockade durch Tyrphostin AG 490 im neonatalen Mausmodell der obstruktiven Uropathie. Der Effekt von Tyrphostin AG 490 wurde an neonatalen Wildtyp-Mäusen (C57BL/6) studiert, bei denen am 2. Lebenstag eine unilaterale Ureterligatur (UUO) bzw. eine Schein-operation durchgeführt wurde. Die neugeborenen Mäuse erhielten ab dem 2. Lebenstag täglich eine subkutane Injektion mit dem JAK2/STAT3-Inhibitor Tyrphostin AG 490, ent-sprechend erhielt die Kontrollgruppe die Vehikellösung. Am 3., 7., bzw. 14. Lebenstag wurden die Nieren entnommen und immunhistochemisch auf Leukozyteninfiltation, Apoptose, Proliferation, tubuläre Atrophie und interstitielle Fibrose untersucht. Die STAT3-Blockade durch Tyrphostin AG 490 führte zu einer signifikanten Reduktion der Makrophagen- und T Lymphozyteninfiltration. Tyrphostin AG 490 reduzierte auch signi-fikant die Apoptose tubulärer, interstitieller und glomerulärer Zellen in der obstruierten Niere. Die STAT3-Blockade bewirkte außerdem einen signifikanten Anstieg der Proliferation tubulärer Zellen nach Ureterligatur. Bezüglich der interstitiellen Fibrose reduzierte Tyrphostin AG 490 die Anzahl aktivierter Myofibroblasten und die Ablagerung extrazellulärer Matrix. Da die interstitielle Fibrose ein wesentlicher Parameter fortgeschrittener Nierener-krankungen ist und negativ mit der Nierenfunktion korreliert, ist ihre Reduktion durch Tyrphostin AG 490 ein vielversprechendes Ergebnis für die Therapie obstruktiver Uropathien. Zusammenfassend unterbrach die STAT3-Blockade durch Tyrphostin AG 490 erfolgreich den Circulus vitiosus der tubulointerstitiellen Inflammation und renalen Fibrose im neonatalen Mausmodell der obstruktiven Uropathie. Der STAT3 Inhibitor Tyrphostin AG 490 könnte aufgrund seiner nephroprotektiven Wirkung ein neuer therapeutischer Baustein in der Behandlung angeborener obstruktiver Uropathien werden

Die Bedeutung der STAT3-Blockade durch Tyrphostin AG 490 im neonatalen Tiermodell der obstruktiven Uropathie

Angeborene obstruktive Uropathien lösen eine ausgeprägte zytokinvermittelte Entzündungsreaktion in der Niere aus. Pro-inflammatorische Signalwege sind wesentlich an der Aufrechterhaltung dieser Entzündung im Sinne eines Circulus vitiosus beteiligt. Dies führt zu tubulärer Apoptose, tubulärer Atrophie und interstitieller Fibrose. Unter anderem ist daran der „Signal Transducer and Activator of Transkription“ (STAT3) als pro-inflamma-torischer und pro-fibrotischer Transkriptionsfaktor beteiligt. Deshalb untersuchte die vorliegende Arbeit die Bedeutung einer STAT3-Blockade durch Tyrphostin AG 490 im neonatalen Mausmodell der obstruktiven Uropathie. Der Effekt von Tyrphostin AG 490 wurde an neonatalen Wildtyp-Mäusen (C57BL/6) studiert, bei denen am 2. Lebenstag eine unilaterale Ureterligatur (UUO) bzw. eine Schein-operation durchgeführt wurde. Die neugeborenen Mäuse erhielten ab dem 2. Lebenstag täglich eine subkutane Injektion mit dem JAK2/STAT3-Inhibitor Tyrphostin AG 490, ent-sprechend erhielt die Kontrollgruppe die Vehikellösung. Am 3., 7., bzw. 14. Lebenstag wurden die Nieren entnommen und immunhistochemisch auf Leukozyteninfiltation, Apoptose, Proliferation, tubuläre Atrophie und interstitielle Fibrose untersucht. Die STAT3-Blockade durch Tyrphostin AG 490 führte zu einer signifikanten Reduktion der Makrophagen- und T Lymphozyteninfiltration. Tyrphostin AG 490 reduzierte auch signi-fikant die Apoptose tubulärer, interstitieller und glomerulärer Zellen in der obstruierten Niere. Die STAT3-Blockade bewirkte außerdem einen signifikanten Anstieg der Proliferation tubulärer Zellen nach Ureterligatur. Bezüglich der interstitiellen Fibrose reduzierte Tyrphostin AG 490 die Anzahl aktivierter Myofibroblasten und die Ablagerung extrazellulärer Matrix. Da die interstitielle Fibrose ein wesentlicher Parameter fortgeschrittener Nierener-krankungen ist und negativ mit der Nierenfunktion korreliert, ist ihre Reduktion durch Tyrphostin AG 490 ein vielversprechendes Ergebnis für die Therapie obstruktiver Uropathien. Zusammenfassend unterbrach die STAT3-Blockade durch Tyrphostin AG 490 erfolgreich den Circulus vitiosus der tubulointerstitiellen Inflammation und renalen Fibrose im neonatalen Mausmodell der obstruktiven Uropathie. Der STAT3 Inhibitor Tyrphostin AG 490 könnte aufgrund seiner nephroprotektiven Wirkung ein neuer therapeutischer Baustein in der Behandlung angeborener obstruktiver Uropathien werden

Diffuse alveolar hemorrhage in children with interstitial lung disease: Determine etiologies!

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) in children is a rare condition resulting from different underlying diseases. This study aimed at describing characteristics and diagnostic measures in children with ILD (children\u27s interstitial lung disease, chILD) and DAH to improve the diagnostic approach by increasing clinician\u27s awareness of diagnostic shortcomings. PATIENTS AND METHODS: A retrospective data analysis of patients with ILD and DAH treated in our own or collaborating centers between 01/07/1997 and 31/12/2020 was performed. Data on clinical courses and diagnostic measures were systematically retrieved as case-vignettes and investigated. To assess suitability of diagnostic software-algorithms, the Human Phenotype Ontology (HPO) was revised and expanded to optimize conditions of its associated tool the Phenomizer. RESULTS: For 97 (74%) of 131 patients, etiology of pulmonary hemorrhage was clarified. For 34 patients (26%), no underlying condition was found (termed as idiopathic pulmonary hemorrhage, IPH). Based on laboratory findings or clinical phenotype/comorbidities, 20 of these patients were assigned to descriptive clusters: IPH associated with autoimmune features (9), eosinophilia (5), renal disease (3) or multiorgan involvement (3). For 14 patients, no further differentiation was possible. CONCLUSION: Complete and sometimes repeated diagnostics are essential for establishing the correct diagnosis in children with DAH. We suggest assignment of patients with IPH to descriptive clusters, which may also guide further research. Digital tools such as the Phenomizer/HPO are promising, but need to be extended to increase diagnostic accuracy

Vaccinating in Pregnancy: Opportunities and Challenges.

The continuum of preconception, antenatal period, fourth trimester, and interconception period are a critical time for comprehensive care to advance maternal-child health and deliver family-centered care. Immunizations are a key component of this care delivery; however, there are intricacies around indications of vaccinations during this key period. Both active immunity to the individual receiving the vaccine as well as passive immunity passed to the fetus during pregnancy highlight the benefits of this care. Understanding the indications and benefits of vaccine administration during this continuum is critical for providers caring for individuals of reproductive age

Classification of body dysmorphic disorder : What is the advantage of the new DSM-5 criteria?

Objective In DSM-5 the diagnosis of body dysmorphic disorder (BDD) has been subjected to two important changes: Firstly, BDD has been assigned to the category of obsessive–compulsive and related disorders. Secondly, a new criterion has been defined requiring the presence of repetitive behaviors or mental acts in response to appearance concerns. The aims of this study were to report the prevalence rates of BDD based on a DSM-5 diagnosis, and to evaluate the impact of the recently introduced DSM-5 criteria for BDD by comparing the prevalence rates (DSM-5 vs. DSM-IV). Methods BDD-criteria (DSM-IV/DSM-5), dysmorphic concerns, and depressive symptoms, were assessed in a representative sample of the German general population (N = 2129, aged 18–65 years). Results The association between BDD case identification based on DSM-IV and DSM-5 was strong (Phi = .95, p < .001), although point prevalence of BDD according to DSM-5 was slightly lower (2.9%, n = 62 vs. 3.2%, n = 68). Approximately one third of the identified BDD (DSM-5) cases reported time-consuming behavioral acts in response to appearance concerns. In detail, 0.8% of the German general population fulfilled the BDD criteria and reported repetitive acts of at least one hour/day. Conclusions The revised criteria of BDD in DSM-5 do not seem to have an impact on prevalence rates. However, the recently added B-criterion reflects more precisely the clinical symptoms of BDD, and may be useful for distinguishing between various severity levels related to repetitive behaviors/mental acts

Personality traits as vulnerability factors in body dysmorphic disorder

Cognitive behavioural models consider certain personality traits to be risk factors for the development of Body Dysmorphic Disorder (BDD). Research on personality traits in BDD is scarce, therefore this study examined perfectionism, aesthetic sensitivity and the behavioural inhibition system (BIS) in BDD. Furthermore, the association between these personality traits and the extent of dysmorphic concerns was investigated. Individuals with BDD (n=58) and a population based control sample (n=2071), selected from a representative German population survey, completed self-report questionnaires assessing DSM-5 criteria of BDD, dysmorphic concerns, perfectionism, aesthetic sensitivity and BIS-reactivity. Individuals with BDD reported significantly higher degrees of perfectionism as well as of BIS-reactivity compared to the population based control sample, whereas the groups did not differ significantly regarding aesthetic sensitivity. However, for the total sample, each of the personality traits was related dimensionally to dysmorphic concerns. Current BDD models consider perfectionism and aesthetic sensitivity to be vulnerability factors. In addition to these concepts, the present study suggests that BIS-reactivity is related to BDD. Self-reported aesthetic sensitivity was not found to be specifically pronounced in BDD, but along with perfectionism and BIS-reactivity aesthetic sensitivity was generally associated with dysmorphic concerns

Body dysmorphic disorder and nonweight-related body image concerns in individuals with eating disorders

Objective: Research on the prevalence of body dysmorphic disorder (BDD) in individuals with eating disorders (EDs) is scarce. Nonweight-related appearance concerns, which can be considered as variants of BDD concerns, have also rarely been examined in EDs. This study therefore investigates BDD prevalence and nonweight-related appearance concerns in EDs. Method: One hundred individuals with EDs (49 inpatients with anorexia nervosa, 51 inpatients with bulimia nervosa) completed structured diagnostic interviews and self-report questionnaires. Results: Twelve individuals with EDs (12.0%) suffered from comorbid BDD, with their body dysmorphic concerns being unrelated to weight and shape. BDD lifetime-prevalence was 15.0%. There was a high prevalence of dissatisfaction with nonweight-related body features such as skin, hair, teeth, nose, and height (20.8 to 53.5%). Discussion: Findings indicate that BDD is a frequent comorbid disorder in individuals with EDs. Furthermore, along with weight and body shape, nonweight-related appearance concerns are also common in individuals with EDs

Tyrphostin AG490 reduces inflammation and fibrosis in neonatal obstructive nephropathy.

BackgroundCongenital obstructive nephropathy is the main cause of end-stage renal disease in infants and children. Renal insufficiency is due to impaired growth and maturation in the developing kidney with obstruction. Congenital obstructive nephropathy leads to cytokine mediated inflammation and the development of interstitial fibrosis. The Janus kinase-2 (JAK-2) and Signal Transducer and Activator of Transcription'-3 (STAT3) are involved in cytokine production, inflammation, and interstitial fibrosis.MethodsWe studied the role of JAK2/STAT3 in a model of congenital obstructive nephropathy using unilateral ureteral obstruction (UUO) in neonatal mice at the second day of life. Cytokine production, inflammation, and interstitial fibrosis were analyzed in obstructed and sham operated kidneys of neonatal mice treated with or without JAK2/STAT3 inhibitor Tyrphostin AG490. To mimic obstruction and distension, proximal tubular cells were stretched in vitro.ResultsWe show that STAT3 is highly activated in the developing kidney with obstruction and in proximal tubular cells following stretch. JAK2/STAT3 activation mediates cytokine release and leukocyte recruitment into neonatal kidneys after UUO. Pharmacological blockade of JAK2/STAT3 by Tyrphostin AG490 reduced inflammation, tubular apoptosis, and interstitial fibrosis. JAK2/STAT3 blockade decreased pro-inflammatory and profibrotic mediators in tubular cells.ConclusionOur findings provide evidence that JAK2/STAT3 mediates inflammation and fibrosis in the developing kidney with obstruction. Blocking JAK2/STAT3 may prove beneficial in congenital obstructive nephropathy in children