Microangiopathic Anemia of Acute Brucellosis – is it a True TTP?

Thrombotic thrombocytopenic purpura (TTP) is a severe disease, potentially fatal, if not diagnosed and treated promptly. TTP is clinically characterized by the pentad of thrombocytopenia, Coombs-negative hemolytic anemia, fever, renal abnormalities and neurological disturbances. Advances in recent years have delineated the molecular mechanisms of acquired and hereditary TTP

Patterns of salivary microbiota injury and oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation

Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Transplantation was associated with a decrease in oral α diversity in all patients. In contrast to the gut microbiome, an association with overall survival was not detected. Among 135 patients given methotrexate for graft-versus-host disease prophylaxis pre-HSCT, Kingella and Atopobium abundance correlated with future development of severe OM. Posttransplant, Methylobacterium species were significantly enriched in patients with severe OM. Moreover, the oral microbiome and metabolome of severe OM patients underwent distinct changes post-HSCT, compared with patients with no or mild OM. Changes in specific metabolites were well explained by microbial composition, and the common metabolic pathway was the polyamines pathway, which is essential for epithelial homeostasis. Together, our findings suggest that salivary microbial composition and metabolites are associated with the development of OM, offering new insights on pathophysiology and potential avenues of intervention

Expert panel diagnosis demonstrated high reproducibility as reference standard in infectious diseases

Objective: If a gold standard is lacking in a diagnostic test accuracy study, expert diagnosis is frequently used as reference standard. However, interobserver and intraobserver agreements are imperfect. The aim of this study was to quantify the reproducibility of a panel diagnosis for pediatric infectious diseases. Study Design and Setting: Pediatricians from six countries adjudicated a diagnosis (i.e., bacterial infection, viral infection, or indeterminate)for febrile children. Diagnosis was reached when the majority of panel members came to the same diagnosis, leaving others inconclusive. We evaluated intraobserver and intrapanel agreement with 6 weeks and 3 years’ time intervals. We calculated the proportion of inconclusive diagnosis for a three-, five-, and seven-expert panel. Results: For both time intervals (i.e., 6 weeks and 3 years), intrapanel agreement was higher (kappa 0.88, 95%CI: 0.81-0.94 and 0.80, 95%CI: NA)compared to intraobserver agreement (kappa 0.77, 95%CI: 0.71-0.83 and 0.65, 95%CI: 0.52-0.78). After expanding the three-expert panel to five or seven experts, the proportion of inconclusive diagnoses (11%)remained the same. Conclusion: A panel consisting of three experts provides more reproducible diagnoses than an individual expert in children with lower respiratory tract infection or fever without source. Increasing the size of a panel beyond three experts has no major advantage for diagnosis reproducibility

Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT

The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) kappa B signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease.Funding Agencies|German Federal Ministry of Education and Research [BMBF 01EO1303]; Deutsche Forschungsgemeinschaft [DFG WA 1597/4-1]; Hebrew University; Hadassah Medical Center; Excellence Initiative of the German Research Foundation (Spemann Graduate School) [GSC-4]</p