Abstract DFNA1 (deafness, nonsyndromic autosomal dominant 1), initially identified as nonsyndromic sensorineural hearing loss, has been associated with an additional symptom: macrothrombocytopenia. However, the timing of the onset of hearing loss (HL) and thrombocytopenia has not been investigated, leaving it unclear which occurs earlier. Here, we generated a knock‐in (KI) DFNA1 mouse model, diaphanous‐related formin 1 ( DIA1 ) KIΔv3/KIΔv3 , in which Aequorea coerulescens green fluorescent protein ( AcGFP ) ‐ tagged human DIA1(p.R1213X) was knocked into the ATG site of Dia1 . Additionally, the exon 7 of Dia1 was deleted using genome editing to knock out (KO) Dia1‐v3, a specific variant of Dia1 . AcGFP‐DIA1(p.R1213X) expression and endogenous DIA1 KO were confirmed in cochleae and platelets. Hearing function in DIA1 KIΔv3/KIΔv3 , but not DIA1 KIΔv3/+ mice, evaluated by auditory brainstem response, was significantly worse at low frequencies compared to wild‐type (WT) mice starting at 3 months of age (3M), with progressive deterioration. Using confocal microscopy and scanning electron microscopy, various stereociliary deformities were identified in the cochleae of DIA1 KIΔv3/KIΔv3 mice. Platelet counts in DIA1 KIΔv3/KIΔv3 , but not DIA1 KIΔv3/+ mice, were significantly lower than those in WT mice at 12M, but not at 6M. Furthermore, in a cohort of eight patients with DFNA1 harboring the p.R1213X mutation, HL preceded thrombocytopenia in three individuals. Thus, in both mice and humans, though HL and thrombocytopenia are progressive, HL manifests earlier than thrombocytopenia. Unlike myosin heavy chain 9 (MYH9) ‐related diseases, thrombocytopenia cannot be a predictive marker for HL in DFNA1. Nevertheless, monitoring platelet counts could provide insights into the progression of the hearing impairments in patients with DFNA1.
Abstract Autophagy occurs in human neutrophils after the phagocytosis of multidrug-resistant bacteria and drug-sensitive strains, including Escherichia coli and Pseudomonas aeruginosa. The present study detected autophagy by immunoblot analysis of LC3B conversion, by confocal scanning microscopic examination of LC3B aggregate formation and by transmission electron microscopic examination of bacteria-containing autophagosomes. Patients with severe bacterial infections are often treated with IVIG alongside antimicrobial agents. Here, we showed that IVIG induced neutrophil-mediated phagocytosis of multidrug-resistant strains. Compared with untreated neutrophils, neutrophils exposed to IVIG showed increased levels of bacterial cell killing, phagocytosis, O2− release, MPO release, and NET formation. IVIG also increased autophagy in these cells. Inhibiting the late phase of autophagy (fusion of lysosomes with autophagosomes) with bafilomycin A1-reduced, neutrophil-mediated bactericidal activity. These findings indicate that autophagy plays a critical role in the bactericidal activity mediated by human neutrophils. Furthermore, the autophagosomes within the neutrophils contained bacteria only and their organelles only, or both bacteria and their organelles, a previously undocumented observation. Taken together, these results suggest that the contents of neutrophil autophagosomes may be derived from specific autophagic systems, which provide the neutrophil with an advantage. Thus, IVIG promotes the neutrophil-mediated killing of multidrug-resistant bacteria as well as drug-sensitive strains.
The association of iron overload with complications of allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested in previous studies. Because hepcidin plays a central role in the regulation of iron homeostasis, we analyzed the association between pretransplant serum hepcidin-25 levels and early infectious complications after allogeneic HSCT. We studied 55 consecutive adult patients with a median age of 47 years (range: 20–64 years) who underwent allogeneic HSCT for hematologic malignancies at our institution. Thirty-two patients had myelogenous malignancies; the remaining 23 had lymphogenous malignancies. The median pretransplant serum hepcidin level of patients in the study was 21.6 ng/mL (range: 1.4–371 ng/mL), which was comparable to that of healthy volunteers (median: 19.1 ng/mL [range: 2.3–37 ng/mL]; n=17). When cumulative incidences of documented bacterial and cytomegalovirus (CMV) infections at day 100 were compared according to pretransplant hepcidin-25 levels, the incidence of bacterial, but not CMV, infection, was significantly higher in the high-hepcidin group (≥50 ng/mL; n=17) than in the low-hepcidin group (<50 ng/mL; n=38) (65% [95% confidence interval, 38%–82%] versus 11% [3%–23%]; P < .001). This finding was confirmed by multivariate Cox analysis adjusted for confounders, including pretransplant ferritin and C-reactive protein (CRP) levels. No fungal infection was documented in either group. These results suggest that the pretransplant serum hepcidin-25 level may be a useful marker for predicting the risk of early bacterial complications after allogeneic HSCT. Larger prospective studies are, however, warranted to confirm our findings.
The aim of this retrospective study was to evaluate the characteristics of increased bone marrow uptake of 18F-FDG in patients with leukemia who underwent whole-body 18F-FDG PET/CT. The 18F-FDG PET/CT images of 9 patients with histologically proven leukemia were reviewed. The accumulation of 18F-FDG in the bone marrow was evaluated, and was compared with histological subtype, clinical course, and hematological findings. Nine patients (4 males, 5 females; age range, 5–58 years) had increased bone marrow uptake of 18F-FDG, including 6 patients with acute lymphoblastic leukemia, 1 with acute myeloid leukemia, 1 with chronic myeloid leukemia, and 1 with mature B cell neoplasm. Bone marrow uptake was generally diffuse but focal or inhomogeneous uptake was common, especially in the upper and lower extremities. Patients with increased bone marrow uptake of 18F-FDG commonly complained of fever and bone pain. No correlations between 18F-FDG uptake and peripheral blood findings were observed. Patients with leukemia may have increased bone marrow uptake of 18F-FDG on PET/CT, possibly reflecting leukemic cell activity. Leukemia can be included in the differential diagnosis when increased bone marrow uptake of 18F-FDG is observed.
