Characterization of a patient with atypical amegakaryocytic thrombocytopenia

We report a 6-year-old girl with amegakaryocytic thrombocytopenia, the first case of this rare congenital disorder not to have an MPL gene mutation. Although no mutations were identified in MPL, Mpl protein was absent in the platelets and TPO induced phosphorylation of the Janus tyrosine kinase 2 (Jak2) was not detected. In addition to the defect of Mpl, the patient demonstrated markedly reduced expression of glycoprotein VI (GPVI) in contrast to normal expression of other platelet-specific proteins GPIb alpha, GPIb beta, and GPIIb. To explore the causes for the absence of Mpl, the entire coding region of Jak2 and AML1 were sequenced and no mutations were identified. To our knowledge, this is the first report that describes a case of amegakaryocytic thrombocytopenia that is not caused by a mutation in MPL and demonstrates the severe impairment of GPVI expression on platelets.     

Two cases of allergic bronchopulmonary mycosis caused by Schizophyllum commune in young asthmatic patients]

We report on two patients, a 27-year-old and a 33-year-old woman, with allergic bronchopulmonary mycosis (ABPM) caused by the basidiomycetous fungus Schizophyllum commune (S. commune). Each patient had bronchial asthma. Both were admitted to our institution for further examination of cough, sputum, and abnormal chest shadows. ABPM was strongly suspected, because they showed eosinophilia in both peripheral blood and sputum, and increased serum IgE levels. A mold was isolated from their sputum, but identification was not possible. Systemic corticosteroid therapy relieved their symptoms and chest abnormal shadows. Later, S. commune, a basidiomycetous fungus, was detected from further examination of their sputum cultures, and serum anti-S. commune IgG was elevated. Finally, both cases were diagnosed as ABPM caused by S. commune. It is reported that this syndrome typically develops in women in middle age, but our patients were young women. It is important to take into account the possibility of ABPM caused by S. commune even in young patients when Aspergillus species are not isolated.     

The effect and possible clinical efficacy of in vivo inhibition of neutrophil extracellular traps by blockade of PI3K-gamma on the pathogenesis of microscopic polyangiitis

Objective: Neutrophil extracellular traps (NETs) are peculiar structures composed of the externalized chromatin with intracellular proteins and formed by activated neutrophils in a reactive oxygen species (ROS)-dependent manner. Aberrant NETs are considered to be autoantigens for anti-neutrophil cytoplasmic antibodies (ANCAs) underling the development of microscopic polyangiitis (MPA). However, little is known regarding the therapeutic efficacy of in vivo inhibition of NET formation (NETosis) on MPA pathogenesis. This study determines whether reducing NETosis prevents ANCA production and improves characteristic involvement.

Methods: A mouse model of MPA induced by administering a novel extract from Candida albicans was devised. By applying this method to mice lacking phosphoinositide 3-kinase gamma (PI3K-gamma), which is indispensable for ROS production in neutrophils, we investigated the levels of in vivo NETs, ANCA titers and histological damage.

Results: Our model exhibited accumulation of NETs in vivo, elevation of ANCA titers and characteristic pathologies mimicking human MPA, including small-vessel vasculitis and crescentic glomerulonephritis. Strikingly, these abnormalities were reduced by genetically and/or pharmacologically blocking PI3K-gamma. Moreover, a pharmacological PI3K-gamma blockade decreased the levels of human NETs.

Conclusion: Our results suggest that in vivo inhibition of NETosis by blocking PI3K-gamma could be a promising therapeutic strategy for the pathogenesis of MPA.     

Clinical significance of high-molecular weight form of adiponectin in male patients with coronary artery disease.

BACKGROUND: It has been reported previously that the measurement of plasma total adiponectin level is clinically useful to estimate the risk of coronary artery disease (CAD). Here, the relevance of high molecular weight (HMW) adiponectin with risk factors for atherosclerosis is investigated METHODS AND RESULTS: A total of 186 consecutive male CAD patients participated in the study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. In contrast, low molecular weight adiponectin levels (which were calculated as the Total - HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. On the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. Multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. CONCLUSIONS: Change in the HMW isoform reflects a change in total adiponectin level. Measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients.     

A case of pulmonary involvement of malignant lymphoma with diffuse ground-glass opacity in chest CT]

A chest CT of an 82-year-old woman suffering from general fatigue revealed ground-glass opacities in both lower lung fields. Antibiotics were administered, but the ground-glass opacities developed into air-space consolidation with air-bronchogram. Hematuria was observed and abdominal CT showed multiple retroperitoneal masses, suggesting malignant lymphoma. The case was diagnosed histopathologically as malignant lymphoma (non-Hodgkins) of the diffuse, medium-sized B cell type on the basis of a right inguinal lymph node biopsy. Autopsy results suggested that the malignant lymphoma may have developed from the left adrenal gland. In the lungs, lymphoma cells infiltrated mainly into the interstitial spaces, but also into some alveolar spaces. The ground-glass opacities found in this case may have reflected the infiltration of lymphoma cells into the pulmonary interstitial spaces.     

Acetaldehyde induces granulocyte macrophage colony-stimulating factor production in human bronchi through activation of nuclear factor-kappa B.

Acetaldehyde, a metabolite of alcohol and primary mediator of alcohol-induced asthma, causes bronchoconstriction via histamine release from airway mast cells. Acetaldehyde also is found in cigarette smoke and may cause airway inflammation. The purpose of this study was to determine the effect of acetaldehyde on cytokine production and nuclear factor kappa B (NF-kappa B) activation in human bronchial tissues. Human bronchi were prepared from normal parts of lung tissues resected for lung cancer (n = 11). The bronchi were cultured in the presence of 5 x 10(-4) M of acetaldehyde for 24 hours and the concentrations of eotaxin, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-5, interleukin-8, and regulated on activation, normal T cells expressed and secreted in cultured supernatants were determined by enzyme-linked immunosorbent assay. Tissues also were immunohistochemically stained for NF-kappa Bp65. Acetaldehyde significantly increased GM-CSF production from human bronchi and nuclear translocation of NF-kappa Bp65 in airway epithelium but had no effects on other cytokines. Our findings suggest that acetaldehyde potentially causes airway inflammation via increased GM-CSF production through nuclear translocation of NF-kappa B.