Preparation and in Vitro Characterization of Fatty-Acid Modified Pirarubicin Nanosuspensions Stabilized by Albumin.

Pirarubicin (THP) shows more rapid intracellular uptake, more effective antitumor activity, and less cardiac toxicity, compared to doxorubicin. However, THP is distributed to both tumor and normal tissues indiscriminately. This study aimed to develop a nanosuspension to deliver THP to tumor tissues more efficiently. Fatty-acid-modified THPs (FA-THPs; octanoic acid, dodecanoic acid, palmitic acid-THPs) were synthesized to increase the hydrophobicity of THP. Nanosuspensions of these FA-THPs were then prepared using an antisolvent precipitation technique. Among the FA-THPs, the most efficiently drug-loaded nanosuspension was obtained from palmitic acid-THP (pal-THP) using an aqueous antisolvent containing bovine serum albumin as a stabilizer. The pal-THP nanoparticles in the nanosuspension were confirmed to be of optimal size (100-125 nm) for delivery to tumor tissues using dynamic light scattering and transmission electron microscopy. The pal-THP nanosuspension showed cytotoxicity in colon 26 cells. The nanosuspension was shown to disintegrate in the presence of surfactants such as lecithin, liberating pal-THP, which was converted to free THP in acidic media. It is therefore proposed that pal-THP nanoparticles that reach tumor cells after intravenous administration would exert antitumor effect by liberating pal-THP (i.e., disintegration of nanoparticles by the interaction with cell membrane), followed by the release of free THP in the acidic milieu of tumor cells. These findings indicate that FA-THP nanosuspensions, particularly pal-THP nanosuspension, hold promise as a candidate for cancer treatment. However, further in vivo studies are necessary.

Effect of Benralizumab on Mucus Plugs in Severe Eosinophilic Asthma.

INTRODUCTION: Mucus plugs are associated with airway obstruction in severe asthma and are involved in the formation of activated eosinophils. Benralizumab, an anti-interleukin-5 receptor antibody, markedly reduces not only peripheral blood eosinophils but also airway eosinophils; however, its effects on mucus plugs have not been clarified. In this study, we examined the efficacy of benralizumab on mucus plugs using computed tomography (CT) imaging. METHODS: Twelve patients who were administered benralizumab and underwent CT before and approximately 4 months after the introduction of benralizumab were included in this study, and the number of mucus plugs before and after benralizumab administration was compared. The correlation between the clinical background and treatment effect was also examined. RESULTS: The number of mucus plugs significantly decreased after the introduction of benralizumab. The number of mucus plugs was correlated with sputum eosinophil percentage and eosinophil cationic protein in the sputum supernatants and inversely correlated with forced expiratory volume in 1 s (FEV1). Benralizumab induction resulted in a marked decrease in blood and sputum eosinophil levels and a significant improvement in asthma symptoms, quality of life scores, FEV1, and exacerbation frequency. Furthermore, there was a significant correlation between the reduction in mucus plugs and changes in the symptom score or FEV1. DISCUSSION/CONCLUSION: These data suggest that benralizumab may have the potential to improve symptoms and respiratory function in patients with severe eosinophilic asthma by reducing mucus plugs.

Effects of Benralizumab on Three-Dimensional Computed Tomography Analysis in Severe Eosinophilic Asthma.

INTRODUCTION: Benralizumab, an anti-interleukin-5 receptor chain monoclonal antibody, is used to treat severe asthma and control asthma symptoms or exacerbations. The aim of this study was to examine the changes in airway morphology using computed tomography (CT) images in accordance with clinical efficacy following the administration of benralizumab. METHODS: The clinical efficacy of benralizumab was evaluated in 11 patients with severe asthma by analyzing the changes in parameters, such as the asthma control test, asthma quality of life questionnaire, pulmonary function, and exacerbation count. We also investigated the airway wall thickness of the right bronchus (B1) and the total airway count (TAC) using CT images. RESULTS: Most patients treated with benralizumab showed improvements in asthma symptoms and exacerbations. CT imaging analyses showed a decrease in the right B1 airway wall thickness and an increase in the TAC. Correlations between blood eosinophil count and changes in CT imaging were observed. DISCUSSION/CONCLUSION: The data suggested that benralizumab has the potential to improve airway wall thickening and ventilation by alleviating the obstruction and clearing an obstructed airway.

Marked reduction in the incidence of transfusion-transmitted hepatitis B virus infection after the introduction of antibody to hepatitis B core antigen and individual donation nucleic acid amplification screening in Japan.

BACKGROUND: In Japan, 41 million blood donations have been screened for hepatitis B virus (HBV) during the past 8.4 years using individual donation nucleic acid amplification testing (ID-NAT) and antibody to hepatitis B core antigen (anti-HBc) screening. STUDY DESIGN AND METHODS: Transfusion-transmitted HBV infection (TT-HBV) incidence was examined. Donated blood implicated in TT-HBV was analyzed for infection stage and DNA levels. Causative HBV strains were phylogenetically analyzed. RESULTS: Among 5162 (0.013%) ID-NAT positives, window period (WP) and occult HBV infection (OBI) accounted for 3.4% (176) and 11.5% (594), respectively. No OBI-related TT-HBV occurred. Seven blood donations caused eight TT-HBV cases, six of which were in the pre-ID-NAT WP, leaving one with an unresolved infection stage. Seven cases were caused by platelet concentrate (180 mL plasma) and one case by fresh-frozen plasma (200 mL plasma), which contained estimated infectious doses varying between 2 and 2300 HBV virions. HBV subgenotypes in five cases were HBV/A2. Complete genome sequences of the transmitting A2 strains were nearly identical (99.6%-100%) and clustered in a group that included HBV/HIV-1 coinfections and a higher proportion of donors in the acute infection phase (69%) than the other group of HBV/A2 sequences (5%). DISCUSSION: The incidence of observed TT-HBV cases has significantly reduced to 0.19 per million in the ID-NAT screening period. OBI-related TT-HBV was eliminated by anti-HBc screening. Established TT-HBV cases were caused by blood products with large plasma volumes containing extremely low HBV concentrations derived from blood donors at a very early infection stage.

Methylmercury directly modifies the 105th cysteine residue in oncostatin M to promote binding to tumor necrosis factor receptor 3 and inhibit cell growth.

We previously found that methylmercury induces expression of oncostatin M (OSM), which is released extracellularly and binds to tumor necrosis factor receptor 3 (TNFR3), possibly enhancing its own toxicity. However, the mechanism by which methylmercury causes OSM to bind to TNFR3 rather than to its known receptors, OSM receptor and LIFR, is unknown. In this study, we aimed to elucidate the effect of methylmercury modification of cysteine residues in OSM on binding to TNFR3. Immunostaining of TNFR3-V5-expressing cells suggested that methylmercury promoted binding of OSM to TNFR3 on the cell membrane. In an in vitro binding assay, OSM directly bound to the extracellular domain of TNFR3, and this binding was promoted by methylmercury. Additionally, the formation of a disulfide bond in the OSM molecule was essential for the binding of both proteins, and LC/MS analysis revealed that methylmercury directly modified the 105th cysteine residue (Cys105) in OSM. Next, mutant OSM, in which Cys105 was replaced by serine or methionine, increased the binding to TNFR3, and a similar effect was observed in immunoprecipitation using cultured cells. Furthermore, cell proliferation was inhibited by treatment with Cys105 mutant OSMs compared with wildtype OSM, and this effect was cancelled by TNFR3 knockdown. In conclusion, we revealed a novel mechanism of methylmercury toxicity, in which methylmercury directly modifies Cys105 in OSM, thereby inhibiting cell proliferation via promoting binding to TNFR3. This indicates a chemical disruption in the interaction between the ligand and the receptor is a part of methylmercury toxicity.

A Promising Needle-Free Pyro-Drive Jet Injector for Augmentation of Immunity by Intradermal Injection as a Physical Adjuvant.

Current worldwide mRNA vaccination against SARS-CoV-2 by intramuscular injection using a needled syringe has greatly protected numerous people from COVID-19. An intramuscular injection is generally well tolerated, safer and easier to perform on a large scale, whereas the skin has the benefit of the presence of numerous immune cells, such as professional antigen-presenting dendritic cells. Therefore, intradermal injection is considered superior to intramuscular injection for the induction of protective immunity, but more proficiency is required for the injection. To improve these issues, several different types of more versatile jet injectors have been developed to deliver DNAs, proteins or drugs by high jet velocity through the skin without a needle. Among them, a new needle-free pyro-drive jet injector has a unique characteristic that utilizes gunpower as a mechanical driving force, in particular, bi-phasic pyrotechnics to provoke high jet velocity and consequently the wide dispersion of the injected DNA solution in the skin. A significant amount of evidence has revealed that it is highly effective as a vaccinating tool to induce potent protective cellular and humoral immunity against cancers and infectious diseases. This is presumably explained by the fact that shear stress generated by the high jet velocity facilitates the uptake of DNA in the cells and, consequently, its protein expression. The shear stress also possibly elicits danger signals which, together with the plasmid DNA, subsequently induces the activation of innate immunity including dendritic cell maturation, leading to the establishment of adaptive immunity. This review summarizes the recent advances in needle-free jet injectors to augment the cellular and humoral immunity by intradermal injection and the possible mechanism of action.

Effect of Dupilumab on Depression in Asthma with Eosinophilic Chronic Rhinosinusitis in the Japanese Population.

INTRODUCTION: Psychological disorders, such as depression, are markedly prevalent in patients with airway diseases. In this study, we assessed the effect of treatment with dupilumab, an IL-4 receptor α chain antibody, on depressive symptoms in a cohort of patients with asthma with eosinophilic chronic rhinosinusitis (ECRS). METHODS: The study participants, diagnosed with asthma and ECRS, were assessed for symptoms and quality of life (QOL) scores for asthma and ECRS and medications. The Patient Health Questionnaire-9 (PHQ-9) scores were used to evaluate the depressive state. The depressive symptoms were compared with asthma and ECRS symptoms both at the time of initiation and after 4 months of dupilumab treatment. RESULTS: Ultimately, 31 patients were included in the study. Most patients demonstrated a depressive state that was correlated with the nasal symptom score. In the evaluation 4 months after dupilumab treatment, the PHQ-9 score was significantly reduced, and the decrease was remarkable in patients whose nasal symptom score was reduced by 50% or more. Additionally, the PHQ-9 scores in patients with improved nasal and asthma symptoms were significantly reduced. DISCUSSION/CONCLUSION: Dupilumab may improve QOL in patients with bronchial asthma with ECRS by reducing depressive symptoms through the improvement of clinical symptoms.

Dyspnea and outcome expectations are associated with physical activity in persons with pneumoconiosis: a cross-sectional study.

BACKGROUND: There are various reports on factors associated with physical activity in patients with chronic respiratory diseases. However, there are no studies on the relationship between physical activity and psychological or environmental factors. In this study, we investigated the relationship between physical activity and psychological and environmental factors using questionnaires for patients with pneumoconiosis. METHODS: This cross-sectional study included patients with pneumoconiosis who underwent a pneumoconiosis health examination in 2019. A self-administered questionnaire was used to conduct the study. Physical activity was evaluated using the International Physical Activity Questionnaire, and subjective symptoms [dyspnea and quality of life (QOL)], environmental factors (environment around home and life space), psychological factors (depression, stage of change, self-efficacy, decisional balance, and outcome expectations), and others (e.g., experience with pulmonary rehabilitation) were investigated. RESULTS: The number of respondents in the study was 185 (men: 171, women: 14). Age, dyspnea, stage of change, self-efficacy, outcome expectations, QOL, depression, decisional balance, and life space were significantly correlated with physical activity. In the multivariate analysis, outcome expectations and dyspnea were extracted as independent factors. In the path analysis, outcome expectations and dyspnea had a direct influence on physical activity. Dyspnea directly impacted not only physical activity but also outcome expectations, stage of change, QOL, life space, and depression. CONCLUSIONS: Dyspnea and outcome expectations were associated with physical activity in patients with pneumoconiosis. To improve physical activity in pneumoconiosis patients, it was suggested that it may be necessary to improve dyspnea and promote an understanding of physical activity.

[A case of foveolar-type gastric adenocarcinoma with a raspberry-like appearance followed up by endoscopy].

A 47-year-old man was referred to our hospital for detailed examination of a gastric polypoid lesion. Esophagogastroduodenoscopy revealed a raspberry-like polyp at the gastric body. Pathological examination of the biopsy specimen revealed this polypoid lesion to be a gastric adenocarcinoma. Endoscopic submucosal dissection was performed, and histopathological examination revealed that lesion to be a well-differentiated adenocarcinoma. Immunohistochemical staining showed that the neoplasm was positive for MUC5AC and negative for MUC6, CD10, and pepsinogen I, indicating that this lesion was a foveolar-type gastric adenocarcinoma. From about 10 years now, this patient has been undergoing esophagogastroduodenoscopy almost every year. This lesion was absent until six years ago. Five years ago, a small polypoid lesion appeared at the gastric body, and this lesion gradually enlarged. The present case showed the growing process of the foveolar-type gastric adenocarcinoma with a raspberry-like appearance.

Factors affecting the recovery of hepatic reserve after sustained virologic response by direct-acting antiviral agents in chronic hepatitis C virus-infected patients.

BACKGROUND AND AIM: Since the advent of direct-acting antiviral (DAA) therapy, the total eradication of hepatitis C virus has been achievable with the recovery of hepatic reserve after achievement of sustained virologic response (SVR). Hence, here, we examined the factors affecting the recovery of hepatic reserve. METHODS: We followed up 403 patients (male: 164, female: 239; genotype 1: 299, genotype 2: 104; median age: 69 years) for at least 3 years after they achieved SVR to DAA therapy. Of these patients, 75 (18.6%) had a history of hepatocellular carcinoma (HCC). Biochemical tests were periodically performed, and the hepatic reserve was evaluated based on the albumin-bilirubin grade. We examined background factors such as age, biochemical test results, HCC occurrence and portosystemic shunt by computed tomography. RESULTS: At the start of treatment, the albumin-bilirubin grades were grades 1, 2, and 3 in 241, 157, and 5 patients, respectively, and 3 years later, 117 of 162 (72%) patients with grade 2 or 3 improved to grade 1. Multivariate analysis identified the HCC occurrence after achievement of SVR (hazard ratio [HR]: 3.08, P < 0.0138), male sex (HR: 3.45, P = 0.0143), hemoglobin level of <11.5 g/dL (HR: 4.19, P = 0.0157), the presence of a portosystemic shunt (HR: 3.07, P = 0.0349), and alanine aminotransferase levels <45 U/L (HR: 2.67, P = 0.0425) as factors inhibiting improvement to grade 1. However, old age was not an inhibitory factor. CONCLUSION: Our results demonstrate that hepatic reserve could be improved even in elderly patients over a long course of time.

Cysteinyl Leukotriene Synthesis via Phospholipase A2 Group IV Mediates Exercise-induced Bronchoconstriction and Airway Remodeling.

It is well known that the prevalence of asthma is higher in athletes, including Olympic athletes, than in the general population. In this study, we analyzed the mechanism of exercise-induced bronchoconstriction by using animal models of athlete asthma. Mice were made to exercise on a treadmill for a total duration of 1 week, 3 weeks, or 5 weeks. We analyzed airway responsiveness, BAL fluid, lung homogenates, and tissue histology for each period. In mice that were treated (i.e., the treatment model), treatments were administered from the fourth to the fifth week. We also collected induced sputum from human athletes with asthma and analyzed the supernatants. Airway responsiveness to methacholine was enhanced with repeated exercise stimulation, although the cell composition in BAL fluid did not change. Exercise induced hypertrophy of airway smooth muscle and subepithelial collagen deposition. Cysteinyl-leukotriene (Cys-LT) levels were significantly increased with exercise duration. Montelukast treatment significantly reduced airway hyperresponsiveness (AHR) and airway remodeling. Expression of PLA2G4 (phospholipase A2 group IV) and leukotriene C4 synthase in the airway epithelium was upregulated in the exercise model, and inhibition of PLA2 ameliorated AHR and airway remodeling, with associated lower levels of Cys-LTs. The levels of Cys-LTs in sputum from athletes did not differ between those with and without sputum eosinophilia. These data suggest that AHR and airway remodeling were caused by repeated and strenuous exercise. Cys-LTs from the airway epithelium, but not inflammatory cells, may play an important role in this mouse model.

Serum Anti-interferon-γ Autoantibody Titer as a Potential Biomarker of Disseminated Non-tuberculous Mycobacterial Infection.

PURPOSE: In the past decade, the relationship between naturally occurring interferon-γ-neutralizing autoantibodies (IFNγ-Ab) and disseminated non-tuberculous mycobacteria (NTM) infection has been established. Furthermore, immune suppressive therapy aimed at the suppression of antibody production has shown efficacy as a supportive treatment. However, the nature of antibody behavior and antibody titer during the course of this disease, as well as the pathophysiological significance of IFNγ-Ab, has not yet been fully elucidated. METHODS: Thirteen Japanese subjects suffering from disseminated NTM (dNTM) infection with IFNγ-Ab were evaluated. The fluctuation of IFNγ-Ab titer and the neutralizing capacity against IFN-γ during the course of the disease were retrospectively analyzed. IFNγ-Ab titers in the sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. RESULTS: Serum antibody titers were not constant during the treatment period and varied over the course of the disease. The antibody titer decreased when the disease was improved by anti-mycobacterial treatment (p < 0.01) and increased as the disease progressed (p < 0.05). Even after the antibody titer decreased, the neutralizing capacity against IFN-γ was maintained by individual sera. CONCLUSIONS: Despite the improvement in the pathological condition via treatment, the patients' sera maintained neutralizing capacity against IFN-γ. Antibody titer fluctuated over the course of the disease and exhibited potential as a biomarker for judgment of the disease state.

Association of upper and lower airway eosinophilic inflammation with response to omalizumab in patients with severe asthma.

Background: The anti-immunoglobulin E monoclonal antibody, omalizumab, is used to treat severe asthma and has the potential to ameliorate airway inflammation. However, the effect of omalizumab in ameliorating upper airway inflammation has not been fully elucidated. Objective: We investigated the association of upper and lower airway inflammation with the response to omalizumab treatment. Methods: We used the Global Evaluation of Treatment Effectiveness to assess the efficacy of omalizumab in treating 16 patients with severe asthma. We also investigated the symptom score, short-acting ß-agonist inhaler use, pulmonary function, biomarkers, computed tomography scans, and nasal mucosa pathology at omalizumab initiation and after four months of treatment. Results: When the fraction of exhaled nitric oxide (FeNO) and the percentage of sputum eosinophil were used as indicators of lower airway inflammation, positive correlations were found between CD20 B-cell, mast cell, and eosinophil counts in the nasal mucosa. Improved asthma symptoms were observed in 12 of the 16 severe asthma cases. The FeNO and eosinophil levels in the nasal tissue, prior to the administration of omalizumab were predictors of the response to asthma treatment. Conclusions: These findings suggest heterogeneity among people with severe asthma. In addition, the phenotype associated with response to omalizumab, leading to improvement in asthma symptoms, comprises upper airway eosinophilia and high FeNO levels.

A study of factors related to asthma exacerbation using a questionnaire survey in Niigata Prefecture, Japan.

BACKGROUND: As indices of asthma control, exacerbations are equally important with symptoms and respiratory function. Thus, it is critical to recognize the risk factors of exacerbation. OBJECTIVE: We conducted a questionnaire survey of asthma patients in Niigata Prefecture to clarify the factors involved in asthma exacerbation. METHODS: The questionnaire survey was carried out in patients and their physicians from September to October 2014. In 2015, the same sample population also received a questionnaire about current asthma control and exacerbation. RESULTS: One hundred patients experienced asthma exacerbation during the 1-year period. There were significant differences in age, sex, history of hospitalization due to asthma, smoking history, Asthma Control Test, treatment step, and transient steroid treatment history in the previous year between the exacerbation group and non-exacerbation group. On multivariate analysis, there was a significant difference in history of transient steroid therapy, history of hospitalization associated with asthma attacks, and nonsmoking history. Cluster analysis of cases with exacerbation was classified into three clusters. Cluster 1 comprised slightly older cases with smoking history, Cluster 2 had more females, non-smoking and nonatopic cases with uncontrolled symptoms, and Cluster 3 had more females, non-smoking and mild atopic cases. CONCLUSIONS: Our findings suggest that patients with asthma exacerbation in the previous year and nonsmoking females are important targets for the study of asthma exacerbation. The adequate treatment of women patients might be important for the prevention of asthma exacerbation.

Characterization of low adherence population in asthma patients from Japan using Adherence Starts with Knowledge-12.

BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.

Optimal titer of anti-HBs in blood components derived from donors with anti-HBc.

BACKGROUND: The ultimate strategy to cope with transfusion-transmitted hepatitis B virus (HBV) infection caused by transfusion of blood from donors with historical HBV infection is to reject all donors having anti-HBV core antigen (anti-HBc). However, this strategy would result in a huge loss of blood donors and subsequent blood inventory collapse. On the other hand, anti-HBc-positive blood is reportedly not infectious when containing more than 100 mIU/mL of anti-HBV surface antigen (anti-HBs). STUDY DESIGN AND METHODS: In Japan, anti-HBc-positive blood has been used for transfusion if it contained 200 mIU/mL or more of anti-HBs. First, to verify the screening policy, clinical outcomes for transfusion of such blood were analyzed for the 2008-2012 period. Second, human hepatocyte-repopulated severe combined immunodeficiency mice were inoculated with HBV preincubated with varying doses of anti-HBs, then viremic status was followed. The effects of anti-HBs across different HBV genotypes were also investigated. RESULTS: Twenty-three transfusion-transmitted HBV infections related to anti-HBc-positive blood components were identified. None of the blood responsible for these cases contained 200 mIU/mL or more of anti-HBs. When 100 µL of plasma containing 104 copies of HBV and 20 mIU of anti-HBs was injected into severe combined immunodeficiency mice, no viremia was detected within 13 weeks. Genotype C anti-HBs was capable of total inhibition of genotype A HBV replication, whereas genotype A anti-HBs inhibited genotype C HBV to a lesser extent. CONCLUSION: Anti-HBc-positive blood containing 200 mIU/mL or more of anti-HBs appears safe as a transfusion component. HBV vaccination seems effective between HBV genotypes A and C.

Clinical Significance of Interferon-γ Neutralizing Autoantibodies Against Disseminated Nontuberculous Mycobacterial Disease.

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

Three-dimensional morphological analysis of the human sacroiliac joint: influences on the degenerative changes of the auricular surfaces.

The sacroiliac joint (SIJ) is responsible for weight transmission between the spine and lower extremity. However, details of the structure and function of the SIJ remain unclear. In a previous study, we devised a method of quantitatively evaluating the level of degeneration of the SIJ using an age estimation procedure for the auricular surface of the ilium. Our results in that study suggested that the degree of degeneration of the joint surface may be associated with the morphology of the auricular surface of the ilium. In that study, however, the morphology of the auricular surface of the ilium was simplified for analysis, meaning that more detailed investigations were required in future. In the present study, we focused on individual differences in the shape of SIJ and carried out three-dimensional quantitative evaluation of the morphology of the auricular surface of the ilium to ascertain its association with joint degeneration. We produced three-dimensional images of the right auricular surfaces of the ilium of 100 modern Japanese men (age 19-83), and obtained the three-dimensional rectangular coordinates of 11 defined measurement points. We then calculated 16 parameters indicating the morphological characteristics of the auricular surfaces of the ilium from the three-dimensional rectangular coordinates of these measurement points, and used these to perform principal component analysis to investigate trends in the morphology of the auricular surface of the ilium. We found that the morphology of the auricular surface of the ilium could be characterized in terms of (i) size, (ii) concavity of the posterior border and (iii) amount of undulation. An investigation of the correlation between these parameters and age suggested that the amount of undulation of the auricular surface of the ilium tends to diminish with advancing age. In an investigation of the association between morphology of the auricular surface of the ilium and degeneration of the articular surface when the subjects were divided into a high-degeneration group (n = 55) and a low-degeneration group (n = 45) and the 16 parameters were compared, there was a significant difference in the amount of undulation of the auricular surface of the ilium. In an investigation limited to older subjects aged ≥ 60 (n = 47) at the time of death, there were significant differences between the high-degeneration group (n = 27) and low-degeneration group (n = 20) in terms not only of the parameters indicating the amount of undulation of the auricular surface of the ilium but also of those indicating the amount of the concavity of the posterior border. These results suggested that the amount of undulation of the auricular surface of the ilium may affect the degree of degeneration of the articular surface. In addition, in older subjects, the degree of concavity of the posterior border of the SIJ may also affect the degree of degeneration of the articular surface. It is thus likely that differences in the morphology of the auricular surface of the ilium may affect degenerative changes in the SIJ.

Sequence analyses of variable cytomegalovirus genes for distinction between breast milk- and transfusion-transmitted infections in very-low-birth-weight infants.

BACKGROUND: Cytomegalovirus (CMV) transmission to very-low-birth-weight infants (VLBWIs) sometimes induces serious clinical symptoms. Although breast milk is considered a major source of transmission, transfusion-transmitted CMV (TT-CMV) infection is often suspected when CMV disease develops after transfusion. Thus, it is clinically important to distinguish between transfusion-transmitted and breast milk-transmitted CMV infections. STUDY DESIGN AND METHODS: Study A: The incidence of acquired CMV transmission was prospectively investigated in 65 VLBWIs. Study B: To determine the transmission routes in 18 TT-CMV-suspected VLBWIs who had been reported in our hemovigilance system, we performed polymerase chain reaction for CMV DNA in fed breast milk and/or repository blood samples related to transfused leukoreduced blood products. Furthermore, we evaluated the identity of CMV strains in patients' urine/blood samples and fed breast milk by sequence analyses of variable CMV genes UL139 and UL146. RESULTS: Study A: Acquired CMV infection was found in 4 of 65 VLBWIs (6.2%). Study B: CMV DNA was detected in fed breast milk for 12 of 14 TT-CMV-suspected cases, for which breast milk was available. Furthermore, CMV DNA sequence-matching rates between fed breast milk and patients' urine/blood for both UL139 and UL146 genes were 100% or nearly 100% in 11 patients. In contrast, repository blood samples for 11 of 14 patients were CMV DNA negative. CONCLUSION: CMV is principally transmitted through breast milk in VLBWIs. The risk of TT-CMV seems to be extremely low when using leukoreduced blood products. Sequence analyses of the variable CMV genes are useful for evaluating CMV transmission routes.

Transcranial Magnetic Stimulation Modulates Resting EEG Functional Connectivity Between the Left Dorsolateral Prefrontal Cortex and Limbic Regions in Medicated Patients With Treatment-Resistant Depression.

High-frequency left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to have efficacy in treatment-resistant depression. However, the effects of rTMS on functional connectivity are still not clear. To examine changes in functional connectivity before and after rTMS, resting EEG of 14 patients with treatment-resistant depression was recorded twice at baseline and at week 4, respectively. The EEG data were analyzed using the standardized low-resolution brain electromagnetic tomography (sLORETA). The results reveal that high-frequency left prefrontal rTMS modulates resting EEG functional connectivity between the left dorsolateral prefrontal cortex and limbic regions, including the subgenual cingulate cortex and parahippocampal gyrus.