A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood. OBJECTIVE: To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach. METHODS: This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell-related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period. RESULTS: The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1-5.6) in cluster 1 and 2.3 (95% CI, 1.0-5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥310 IU/mL, blood eosinophil counts ≥280 cells/µL, a higher ratio of TBX21/GATA3, FEV1 /FVC ratio <0.67 and smoking ≥10 pack-years with an area under the curve of 0.94 (95% CI, 0.90-0.98) in the receiver operating characteristic analysis. CONCLUSIONS AND CLINICAL RELEVANCE: The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype.

Understanding the Relationship between Social Cognition and Word Difficulty. A Language Based Analysis of Individuals with Autism Spectrum Disorder.

BACKGROUND: Few quantitative studies have been conducted on the relationship between society and its languages. Individuals with autistic spectrum disorder (ASD) are known to experience social hardships, and a wide range of clinical information about their quality of life has been provided through numerous narrative analyses. However, the narratives of ASD patients have thus far been examined mainly through qualitative approaches. OBJECTIVES: In this study, we analyzed adults with ASD to quantitatively examine the relationship between language abilities and ASD severity scores. METHODS: We generated phonetic transcriptions of speeches by 16 ASD adults at an ASD workshop, and divided the participants into 2 groups according to their Social Responsiveness Scale(TM), 2nd Edition (SRS(TM)-2) scores (where higher scores represent more severe ASD): Group A comprised high-scoring ASD adults (SRS(TM)-2 score: ≥ 76) and Group B comprised low- and intermediate-scoring ASD adults (SRS(TM)-2 score: < 76). Using natural language processing (NLP)-based analytical methods, the narratives were converted into numerical data according to four language ability indicators, and the relationships between the language ability scores and ASD severity scores were compared. RESULTS AND DISCUSSION: Group A showed a marginally negative correlation with the level of Japanese word difficulty (p < .10), while the "social cognition" subscale of the SRS(TM)-2 score showed a significantly negative correlation (p < .05) with word difficulty. When comparing only male participants, Group A demonstrated a significantly lower correlation with word difficulty level than Group B (p < .10). CONCLUSION: Social communication was found to be strongly associated with the level of word difficulty in speech. The clinical applications of these findings may be available in the near future, and there is a need for further detailed study on language metrics designed for ASD adults.

Respiratory mechanics and peripheral airway inflammation and dysfunction in asthma.

BACKGROUND: Clinical application of the forced oscillation technique (FOT) has progressed with the spread of commercially available FOT devices. The correlation between respiratory impedance and spirometry has been reported; however, the association with airway inflammation and pulmonary function, in the lung periphery in particular, is unclear. OBJECTIVE: To assess whether respiratory impedance is associated with peripheral airway inflammation and dysfunction in asthma. METHODS: Subjects included 78 patients with overall controlled asthma. We measured whole-breath or within-breath respiratory system resistance (Rrs) and reactance (Xrs) using a commercially available multi-frequency FOT device (MostGraph-01), and assessed the correlation with the fraction of exhaled nitric oxide (FeNO), alveolar nitric oxide concentration (CANO), maximal NO flux in the conductive airways (J'awNO), and the N2 phase III slope of single breath N2 washout (delta N2 ). RESULTS: The differences between inspiratory and expiratory phases of Xrs at 5 Hz (X5), resonant frequency (Fres), and a low-frequency reactance area (ALX) were significantly correlated with CANO; however, there was no correlation between respiratory impedance and FeNO or J'awNO. The delta N2 values were significantly correlated with whole-breath, inspiratory, and expiratory Rrs and Xrs, except for R20. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that respiratory impedance reflects peripheral airway inflammation and ventilation inhomogeneity.

FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect.

Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization.

[The use of right ventricular support with a centrifugal pump in a case with right ventricular failure due to intraoperative right ventricular infarction].

The patient was 67-year-old woman with mitral valve restenosis and regurgitation, tricuspid insufficiency, and left atrial dilatation who underwent mitral valve replacement, tricuspid valvuloplasty, and left atrial plication. The patient developed right ventricular (RV) failure due to RV infarction when she was weaned from cardiopulmonary bypass (CPB). Therefore, CPB was resumed to be followed by intra-aorta balloon pumping (IABP). However, complete response was not obtained. Thus, right ventricular support was performed using a centrifugal pump, and the patient could be weaned from CPB. Three days after surgery, the right ventricular support was discontinued, and IABP was removed 7 days after surgery without marked changes in hemodynamics. Although RV failure due to RV infarction is a serious intraoperative complication, favorable results were obtained by combination therapy with IABP and right ventricular support using a centrifugal pump in our patient.

Preoperative application of limited cone beam computerized tomography as an assessment tool before minor oral surgery.

We describe the preoperative application of limited cone beam computerized tomography (CT) using a Dental three-dimensional (3D)-CT as an assessment tool before minor oral surgery. The Dental 3D-CT provided 42.7 mm-high and 30 mm-wide rectangular solid images. This size covered the height of the mandible with standing teeth. Dental 3D-CT clearly demonstrated lesions in the maxillary and mandibular bone. Resorption of the bone due to disease expansion was depicted more clearly on the Dental 3D-CT than on conventional radiographs. Information about lesion location and the relationship between the lesions and their adjacent anatomical structures, such as the mandibular canal and maxillary antrum, was useful for minor oral surgery. Due to its high resolution and low radiation dose, Dental 3D-CT was useful for preoperative examination prior to minor oral surgery.

The right retroperitoneal approach on abdominal aortic aneurysm with an isolated left-sided inferior vena cava. Report of a case.

We report herein the case of a 78-year-old man found to have abdominal aortic aneurysm (AAA) with an isolated left-sided inferior vena cava (IVC). The patient was admitted to our hospital to undergo surgery for the AAA. The computed tomography revealed the sacular aneurysm of the infrarenal abdominal aorta (60 x 40 mm) and right common iliac aneurysm (30 x 30 mm). At the same time the left sided IVC was found by the CT. This IVC (13 mm wide) ascended 76 mm, dorsally to the ureter, the left side of the AAA from the right common iliac artery to the left renal artery. We performed aneurysmectomy and 20 mm knitted Dacron bifurcating graft replacement by the right retroperitoneal approach without manipulating the left-sided IVC. The procedure was completed without incident and the patient has continued to do well.

A male patient who developed late-onset primary biliary cirrhosis presenting with antinuclear envelope antibodies.

Abstract An 81-year-old man who had previously shown high levels of alkaline phosphatase (ALP), γ-glutamyltransferase (GTP), and total bilirubin presented with acute liver damage. He was positive for serum anti-gp210 and anti-p62 antibodies, but negative for serum antimitochondrial antibody. A liver biopsy revealed massive interstitial fibrosis and pseudolobulus, which were compatible with a diagnosis of primary biliary cirrhosis (PBC) at Scheuer's stage 4. He was given ursodeoxycolic acid at 600 mg/day. However, his condition deteriorated, and he eventually died of hepatic insufficiency in a state of malnutrition. We hypothesize that the presence of anti-gp210 and anti-p62 complex protein antibodies, rather than that of antimitochondrial antibodies, was correlated with the progression of PBC in this particular case.

Osteoid osteoma in mandibular condyle.

A 21-year-old Japanese woman presented with trismus and spontaneous pain (especially at night) around the left temporomandibular joint. Radiographic examination showed a subcortical sclerosed nodule measuring approximately 8 mm in diameter on the infero-lateral aspect of the left mandibular condyle. Amputation of the condyle was performed under general anesthesia. The patient has been in good condition 8 years postoperatively. The histopathology of the specimen consisted of actively proliferating osteoblasts mixed with an interlacing network of woven bone and osteoid trabeculae. Histopathological diagnosis was osteoid osteoma.

[A successful surgical case of chronic DeBakey IIIb dissecting aortic aneurysm associated with right-sided aortic arch].

A case of chronic DeBakey IIIb dissecting aneurysm associated with right-sided aortic arch and aberrant left subclavian artery is reported. A 51-year-old man was admitted to our institute for surgical treatment of chronic dissecting aortic aneurysm which occurred 3 years ago. A right posterolateral thoracotomy was made through the 4th intercostal space. Closure of entry was performed under temporary hypothermic circulatory arrest and then, this was followed by plication of false lumen under hypothermic CPB. Post-operative clinical course was uneventful and an intra-venous digital subtraction angiography demonstrated that false lumen in the thorax was completely closed. The patient was discharged from the hospital on 21th POD. Dissecting aortic aneurysm associated with right-sided aortic arch is extremely rare. In operative case, pertinent selection of operative methods considering anatomical diversity is required.

Significance of chymase-dependent angiotensin II-forming pathway in the development of vascular proliferation.

BACKGROUND: Vascular tissues of humans and dogs contain chymase as an angiotensin II-forming enzyme. In this study, we investigated whether chymase-dependent angiotensin II formation plays a crucial role in the development of vascular proliferation in dog grafted veins. METHODS AND RESULTS: The right external jugular vein of dogs was grafted to the ipsilateral carotid artery. As a control group, the right external jugular veins in dogs that had not received grafts were used. In the chymase inhibitor-treated group, the vein was infiltrated with 10 micromol/L Suc-Val-Pro-Phe(P)(OPh)(2) and was grafted to the carotid artery. In the placebo-treated group, ACE activity in the grafted veins was significantly lower than that in the control veins up to 7 days after the operation, whereas chymase activity was increased significantly. After 7 days, the mRNA levels of collagen I, collagen III, and fibronectin, all of which are induced by an increase of angiotensin II action, were significantly increased in the grafted veins, and the intima-media ratio of the grafted veins was also increased. In the chymase inhibitor-treated group, the chymase activity in the grafted veins 7 days after the operation was suppressed to 12.1%. The elevated mRNA levels of fibronectin, collagen I, and collagen III in the grafted veins were significantly suppressed by treatment with the chymase inhibitor, and the intima-media ratio was also decreased significantly. CONCLUSIONS: We demonstrate for the first time that chymase-dependent angiotensin II formation plays an important role in the development of vascular proliferation in the grafted veins.

[A recurrent case of idiopathic interstitial pneumonia histologically diagnosed as nonspecific interstitial pneumonia group 1].

A 59-year-old man was admitted to our hospital because of dyspnea. Chest radiography showed infiltration and consolidation in both lung fields. He was clinically diagnosed as having idiopathic interstitial pneumonia (IIP), and histological examination of a thoracoscopic lung biopsy specimen showed nonspecific interstitial pneumonia (NSIP) group 1. Corticosteroid therapy had previously been effective, but about 1 year later the disease recurred. The patient's clinical condition was very similar to the first episode, and is improving in response to the same treatment again. Although it is generally accepted that patients with IIP diagnosed histologically as NSIP have a good prognosis, it should be remembered that recurrence is possible, even in patients with group 1.

[Plication of the sinotubular junction for aneurysm of the ascending aorta associated with aortic regurgitation: a case report].

A 63-year-old woman with aneurysm of the ascending aorta associated with AR due to dilatation of the sinotubular junction (STJ) and with poor LV function, who did not have Marfan syndrome, underwent a plication of the STJ and replacement of the ascending aorta. In operation, we simultaneously performed the plication of dilated STJ (60 mm) and the replacement of ascending aorta using a 26 mm Woven Dacron graft. Post-operative angiogram (1 POM) showed no aortic regurgitation and good recovery of the LV function. This procedure is less invasive, and indicated for patients without significant elongation or thickening of the aortic valve, especially when the patients have higher risk.

Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus.

The beta-lactam resistance gene mecA of Staphylococcus aureus is carried by a novel mobile genetic element, designated staphylococcal cassette chromosome mec (SCCmec), identified in the chromosome of a Japanese methicillin-resistant S. aureus (MRSA) strain. We now report identification of two additional types of mecA-carrying genetic elements found in the MRSA strains isolated in other countries of the world. There were substantial differences in the size and nucleotide sequences between the elements and the SCCmec. However, new elements shared the chromosomal integration site with the SCCmec. Structural analysis of the new elements revealed that they possessed all of the salient features of the SCCmec: conserved terminal inverted repeats and direct repeats at the integration junction points, conserved genetic organization around the mecA gene, and the presence of cassette chromosome recombinase (ccr) genes responsible for the movements of SCCmec. The elements, therefore, were considered to comprise the SCCmec family of staphylococcal mobile genetic elements together with the previously identified SCCmec. Among 38 epidemic MRSA strains isolated in 20 countries, 34 were shown to possess one of the three typical SCCmec elements on the chromosome. Our findings indicated that there are at least three distinct MRSA clones in the world with different types of SCCmec in their chromosome.

Chymase-dependent angiotensin II formation in the saphenous vein versus the internal thoracic artery.

OBJECTIVES: The great saphenous vein graft is known to be less patent than the internal thoracic artery graft. Recently, we reported that chymase-dependent angiotensin II formation plays an important role in the development of intimal hyperplasia in dog grafted veins. In this study we investigated the levels of angiotensin II-forming enzymes, angiotensin-converting enzyme, and chymase in human saphenous veins and internal thoracic arteries. METHODS: The saphenous vein and internal thoracic artery specimens were obtained from coronary artery bypass grafts of patients during surgical procedures (saphenous vein, n = 16; internal thoracic artery, n = 16). Activities of angiotensin-converting enzyme and chymase were determined by using the extract from the saphenous vein or internal thoracic artery. Sections of the saphenous vein or internal thoracic artery were stained with van Gieson's elastin stain and were immunostained with anti-human chymase antibody. RESULTS: The activities of angiotensin-converting enzyme in the saphenous vein and internal thoracic artery were 0.34 +/- 0.12 and 0.32 +/- 0.17 mU/mg protein, respectively, and the difference was not significant. The chymase activity in the saphenous vein was significantly higher than that in the internal thoracic artery (saphenous vein, 10.1 +/- 0.81 mU/mg protein; internal thoracic artery, 6.21 +/- 1.86 mU/mg protein). Chymase-positive cells in the saphenous vein were located in both the media and adventitia, and those in the internal thoracic artery were located only in the adventitia. The number of chymase-positive cells in the saphenous vein was about 2.6 times that in the internal thoracic artery. CONCLUSION: The chymase activity, but not the angiotensin-converting enzyme activity, was significantly higher in the saphenous vein, suggesting that the high levels of chymase activity may be related to the poorer performance of the saphenous vein for use as a bypass conduit.

Chloroplastic ascorbate peroxidase is the primary target of methylviologen-induced photooxidative stress in spinach leaves: its relevance to monodehydroascorbate radical detected with in vivo ESR.

Methylviologen (MV) induces oxidative damages in leaves. In order to understand its mechanism we studied initial biochemical events under light in MV-fed spinach leaves. When isolated chloroplasts were illuminated in the presence of MV, both stromal and thylakoid-bound ascorbate peroxidases (APX) were inactivated rapidly at the same rates, and their inactivation was retarded by ascorbate (AsA) at higher concentrations. Since MV accelerates the photoproduction of O2- in Photosystem (PS) I and simultaneously inhibits the photoreduction of monodehydroascorbate (MDA) to AsA, the inactivation of APX was attributed to the loss of AsA and accumulation of H2O2 in the stroma. Following APX, superoxide dismutase and NADP(+)-glyceraldehyde 3-phosphate dehydrogenase, both of which are vulnerable to H2O2, were inactivated by MV plus light. Dehydroascorbate reductase, monodehydroascorbate reductase, PS II, PS I and ferredoxin-NADP(+) reductase were far less sensitive to the treatment. In the treated leaves, cytosolic APX and guaiacol-specific peroxidase were also inactivated, but slower than chloroplastic APXs were. Catalase was not inactivated. Thus the MV-induced photooxidative damages of leaves are initiated with the inactivation of chloroplastic APXs and develop via the inactivation of other H2O2-sensitive targets. The decay half-life of the MDA signal after a short illumination in the leaves, as determined by in vivo electron spin resonance spectrometry (ESR), was prolonged when the H2O2-scavenging capacity of the leaf cells was abolished by the inactivation of chloroplastic and cytosolic APXs. The measurement of MDA in leaves by ESR, therefore, allows to estimate in vivo cellular capacity to scavenge the photoproduced H2O2.