Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies

Journal of Clinical Immunology - Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable...     

Sonic Hedgehog Expands Diaphyseal Trabecular Bone Altering Bone Marrow Niche and Lymphocyte Compartment

Bone marrow contains distinct microenvironments that regulate hematopoietic stem cells (HSCs). The endosteal HSC niche includes osteoblasts, mineral, and extracellular matrix proteins that interact through various molecular signals to control HSCs. Sonic hedgehog (Shh) is a morphogen involved in the regulation of skeletal development and hematopoiesis, but the effects of Shh on bone in relation to the HSC niche are not well understood. We demonstrate that systemic overexpression of Shh in mice increases osteoblast number with the resultant formation of new trabeculae in the femoral diaphysis. Suggestive of a functional change in the hematopoietic niche, numbers of Lin⁻ Sca-1⁺ c-Kit⁺ cells with hematopoietic progenitor function expand, although cells with in vivo repopulating capacity in the wild-type environment do not increase. Instead, Shh mediates a decrease in number of bone marrow lymphocytes accompanied by a decreased expression of stromal-derived growth factor 1 (SDF-1) and a decrease in Flk2-expressing Lin⁻ Sca-1⁺ c-Kit⁺ cells, indicating a modulation of early lymphopoiesis. This is caused by a microenvironment-induced mechanism as Shh treatment of bone marrow recipients, but not donors, results in a dramatic depletion of lymphocytes. Together, these data suggest that Shh mediates alterations in the bone marrow hematopoietic niche affecting the early lymphoid differentiation.     

Osteoporose und Mehrlingsgravidit?t - ein Erfahrungsbericht mit positivem Ausgang

Zusammenfassung Hintergrund: Die schwangerschaftsassoziierte Osteoporose ist ein seltenes Ereignis. Deshalb bestehen keine klaren therapeutischen Richtlinien, wobei die Therapie aufgrund der potentiellen Teratogenität vieler Resorptionshemmer ohnehin limitiert ist. Fallbericht: Bei einer 30-jährigen Patientin kam es im Verlauf der ersten Schwangerschaft zu einer Schambeinfraktur. Osteodensitometrisch konnte eine ausgeprägte Osteoporose nachgewiesen werden. Unter Therapie mit Alendronat, 1 000 mg Calcium und 1 000 IE Cholecalciferol/die und sequenzieller Östrogen-/Gestagensubstitution konnte die Knochendichte angehoben werden, lag aber noch im osteoporotischen Bereich, als die Patientin 3 Jahre später erneut schwanger wurde. Nach Absetzen von Alendronat konnte bei bestehender Drillingsschwangerschaft durch Erhöhung der Calciumsupplementation auf 3 000 mg/die und der Cholecalciferolgabe auf 1 500 IE/die ein Status idem zur Knochendichte unmittelbar vor der zweiten Schwangerschaft beibehalten werden. Schlussfolgerung: Mit diesem Konzept könnte der eigentlich in der Schwangerschaft zu befürchtende Knochenmasseverlust verhindert worden sein; dies bedarf aber noch der Überprüfung an größeren Fallzahlen. Abstract Background: Pregnancy-associated osteoporosis is a rare condition. Due to the rareness of pregnancy-associated osteoporosis, no guidelines concerning an adequate therapy exist. However, since many antiresorptive drugs are potentially teratogenous, the therapeutic approach is limited. Case Report: In a 30-year-old patient, pubic fracture occurred during her first pregnancy. Osteodensitometry revealed a distinct osteoporosis. The bone density improved under therapy with sex hormones, alendronate, 1,000 mg calcium and 1,000 IU cholecalciferol daily, but still remained osteoporotic when the patient again became pregnant 3 years later. During her triplet pregnancy the patient was treated with 3,000 mg calcium and 1,500 IU cholecalciferol daily. After delivery the bone density remained at the same level as immediately before the second pregnancy. Conclusion: Regarding the nonoccurrence of the expected considerable bone loss with this treatment the efficacy of this therapeutic approach during pregnancy warrants further study.     

Pulmonary toxicity among cancer patients treated with a combination of docetaxel and gemcitabine: a meta-analysis of clinical trials

Purpose  

The combination of docetaxel and gemcitabine was tested in several studies in patients with lung, breast, and pancreatic cancers and other tumor entities. Some studies reported cases of severe or even fatal pulmonary toxicity that led to early termination of some trials. We created a meta-analysis model of published studies to identify explanatory factors for docetaxel–gemcitabine-dependent pulmonary toxicity.     

Erlotinib in patients with advanced non-small-cell lung cancer: impact of dose reductions and a novel surrogate marker

Erlotinib is a relatively well-tolerated treatment option for patients with advanced non-small-cell lung cancer (NSCLC). Some patients suffer from severe skin toxicity or diarrhea, making dose reductions or even treatment cessation necessary. Recent clinical trials usually defined a 100 mg daily dose as the lowest acceptable dose, whereas little is known about the efficacy with lower doses. We retrospectively reviewed the files of all patients with advanced non-small-cell lung cancer (NSCLC) treated with erlotinib. We assessed demographic, disease- and treatment-related information. We tried to correlate tolerability with clinical efficacy. EGF receptor exon 18/19/21 mutations were analyzed in selected patients. Fifty-three patients with advanced non-small-cell lung cancer were treated with erlotinib. In nine patients (17%), the doses had to be reduced to 75 or 50 mg daily due to toxicity. We observed several sustained disease stabilizations in this subgroup. Patients suffering from paronychia with erlotinib had a significantly longer time to progression than did subjects without nail toxicity (P = 0.04). If patients were free from any toxicity, they were at high risk for early tumor progression (P = 0.001) and death. In patients with disease stabilization for 6 months or longer, we observed EGFR 18/19/21 wild type, exon 19 and exon 21 mutations. In conclusion, several patients required dose reductions during treatment with erlotinib. However, in tumors with sensitivity to erlotinib, even daily doses of 50–75 mg can result in sustained disease control. Paronychia represents a favorable surrogate marker for efficacy.     

NT-proBNP is not elevated in patients with obstructive sleep apnoea

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-ProBNP) has emerged as an important marker of cardiac stress and may reflect the severity of underlying cardiac dysfunction, which is thought to be associated with obstructive sleep apnoea syndrome (OSAS). METHODS: This study evaluated the plasma concentration of NT-ProBNP in 60 consecutive patients (median age 55.7 years, median body mass index (BMI) 31.8) who were referred to a sleep laboratory with a suspicion of OSAS. Each subject underwent measurement of morning NT-ProBNP plasma levels, polysomnography and echocardiography. Patients were treated with nasal continuous or bilevel positive airway pressure ventilation (nCPAP/BIPAP) or without mechanical respiratory support, depending on clinical symptoms and results of polysomnography. Three months after treatment of OSAS 28 of the patients were reassessed for re-evaluation of NT-ProBNP and polysomnography. RESULTS: Low or high levels of NT-proBNP were not associated with AHI and other sleep related indices (p>0.3). There was no correlation between NT-proBNP and AHI or other sleep related indices. In multiple regression analysis, NT-proBNP was significantly correlated with left ventricular ejection fraction, creatinine clearance and the presence of systemic arterial hypertension but not with AHI. CONCLUSIONS: Our results show by a robust multiple regression analysis, that NT-pro BNP is not associated with OSAS and NT-pro BNP cannot be used as a sensitive marker for underlying cardiovascular abnormalities in patients with OSAS.