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.

Anomalous connection of the left posterior renal vein with the left ascending lumbar vein in a Japanese cadaver.

A rare variation was found in one of the two left renal veins in a 94-year-old male cadaver undergoing routine dissection. The characteristic findings in the cadaver included, in addition to the primary left renal vein, the presence of a posterior left renal vein draining to the left ascending lumbar vein without communicating with the inferior vena cava and other renal veins. Variations in the number and arrangement of the vessels terminating in the renal veins are common, but to our knowledge, variation similar to our findings has not been previously reported. This variation may represent an immature form of the complicated development of the renal vessels.

Nationwide surveillance of antimicrobial consumption and resistance to Pseudomonas aeruginosa isolates at 203 Japanese hospitals in 2010.

PURPOSE: In Japan, a national surveillance study of antimicrobial consumption has never been undertaken. This study aimed to describe antimicrobial consumption and resistance to Pseudomonas aeruginosa in 203 Japanese hospitals, to identify targets for quality improvement. METHODS: We conducted an ecological study using retrospective data (2010). Antimicrobial consumption was collected in the World Health Organization (WHO) anatomical therapeutic chemical/defined daily dose (ATC/DDD) format. Rates of imipenem (IPM), meropenem (MEPM), ciprofloxacin (CPFX), or amikacin (AMK) resistance were expressed as the incidence of non-susceptible isolates. Additionally, hospitals were asked to provide data concerning hospital characteristics and infection control policies. Hospitals were classified according to functional categories of the Medical Services Act in Japan. RESULTS: Data were collected from 203 Japanese hospitals (a total of 91,147 beds). The total antimicrobial consumption was 15.49 DDDs/100 bed-days (median), with consumptions for penicillins, carbapenems, quinolones, and glycopeptides being 4.27, 1.60, 0.41, and 0.49, respectively. The median incidences of IPM, MEPM, CPFX, and AMK resistance were 0.15, 0.10, 0.13, and 0.03 isolates per 1,000 patient-days, respectively. Antimicrobial notification and/or approval systems were present in 183 hospitals (90.1 %). In the multivariate analysis, the piperacillin/tazobactam, quinolones, and/or total consumptions and the advanced treatment hospitals showed a significant association with the incidence of P. aeruginosa resistant to IPM, MEPM, CPFX, and AMK [adjusted R (2) (aR (2)) values of 0.23, 0.30, 0.22, and 0.35, respectively). CONCLUSION: This is the first national surveillance study of antimicrobial consumption in Japan. A continuous surveillance program in Japan is necessary in order to evaluate the association among resistance, antimicrobial restriction, and consumption.

Quality of life of Japanese elderly oral cancer patients during the perioperative period.

Japan's aging society has an increasing incidence of oral cancer. This study investigated perioperative changes in quality of life (QoL) among 172 oral cancer patients (elderly ≥75 years vs non-elderly <75 years), pre-treatment, at treatment completion, and at 1, 3, and 6 months post-treatment, using the following Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) subscales: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), additional head- and neck-specific concerns (H&N). SWB (P=0.026), H&N (P=0.024), and total FACT-H&N (P=0.009) scores were significantly lower in the elderly group than in the non-elderly group at 6 months post-treatment, especially for mastication items (H&N1, P=0.047; H&N11, P=0.004), but not for swallowing items (H&N5 and H&N7, both P> 0.05). PWB (P= 0.004), EWB (P< 0.001), and FWB (P= 0.022) scores in the non-elderly group were significantly higher at 6 months post-treatment than before treatment. In the elderly group, no subscale showed a better score at 6 months post-treatment. Post-treatment QoL in elderly oral cancer patients did not improve, unlike in non-elderly patients.

Scanning sonar of rolling porpoises during prey capture dives.

Dolphins and porpoises have excellent biosonar ability, which they use for navigation, ranging and foraging. However, the role of biosonar in free-ranging small cetaceans has not been fully investigated. The biosonar behaviour and body movements of 15 free-ranging finless porpoises (Neophocaena phocaenoides) were observed using electronic tags attached to the animals. The porpoises often rotated their bodies more than 60 deg., on average, around the body axis in a dive bout. This behaviour occupied 31% of the dive duration during 186 h of effective observation time. Rolling dives were associated with extensive searching effort, and 23% of the rolling dive time was phonated, almost twice the phonation ratio of upright dives. Porpoises used short inter-click interval sonar 4.3 times more frequently during rolling dives than during upright dives. Sudden speed drops, which indicated that an individual turned around, occurred 4.5 times more frequently during rolling dives than during upright dives. Together, these data suggest that the porpoises searched extensively for targets and rolled their bodies to enlarge the search area by changing the narrow beam axis of the biosonar. Once a possible target was detected, porpoises frequently produced short-range sonar sounds. Continuous searching for prey and frequent capture trials appeared to occur during rolling dives of finless porpoises. In contrast, head movements ranging +/-2 cm, which can also change the beam axis, were regularly observed during both dives. Head movements might assist in instant assessment of the arbitrary direction by changing the beam axis rather than prey searching and pursuit.

Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions.

UNLABELLED: BACKGROUND" Human thymic stromal lymphopoietin (TSLP) is expressed in the human asthmatic lung and activates dendritic cells (DCs) to strongly induce proallergic T-helper type 2 (Th2) cell responses, suggesting that TSLP plays a critical role in the pathophysiology of human asthma. Th2 cells are predominantly involved in mild asthma, whereas a mixture of Th1 and Th2 cells with neutrophilic inflammation, probably induced by Th17, affects more severe asthmatic disease. Exacerbation of asthmatic inflammation is often triggered by airway-targeting RNA viral infection; virus-derived double-stranded RNA, Toll-like receptor (TLR)3 ligand, activates bronchial epithelial cells to produce pro-inflammatory mediators, including TSLP. OBJECTIVE: Because TSLPR-expressing DCs express TLR3, we examined how the relationship between TSLP and TLR3 ligand stimulation influences DC activation. METHODS: CD11c(+)DCs purified from adult peripheral blood were cultured in TLR ligands containing media with or without TSLP and then co-cultured with allogeneic naïve CD4(+)T cells. RESULTS: CD11c(+) DCs responded to a combination of TSLP and TLR3 ligand, poly(I : C), to up-regulate expression of the functional TSLP receptor and TLR3. Although TSLP alone did not induce IL-23 production by DCs, poly(I : C) alone primed DCs for the production of IL-23, and a combination of TSLP and poly(I : C) primed DCs for further production of IL-23. The addition of poly(I : C) did not inhibit TSLP-activated DCs to prime naïve CD4(+) T cells to differentiate into inflammatory Th2 cells. Furthermore, DCs activated by a combination of TSLP and poly(I : C) primed more naïve CD4(+) T cells to differentiate into Th17-cytokine-producing cells with a central memory T cell phenotype compared with DCs activated by poly(I : C) alone. CONCLUSIONS: These results suggest that through DC activation, human TSLP and TLR3 ligands promote differentiation of Th17 cells with the central memory T cell phenotype under Th2-polarizing conditions.

Human TSLP directly enhances expansion of CD8+ T cells.

Human thymic stromal lymphopoietin (TSLP) promotes CD4(+) T-cell proliferation both directly and indirectly through dendritic cell (DC) activation. Although human TSLP-activated DCs induce CD8(+) T-cell proliferation, it is not clear whether TSLP acts directly on CD8(+) T cells. In this study, we show that human CD8(+) T cells activated by T-cell receptor stimulation expressed TSLP receptor (TSLPR), and that TSLP directly enhanced proliferation of activated CD8(+) T cells. Although non-stimulated human CD8(+) T cells from peripheral blood did not express TSLPR, CD8(+) T cells activated by anti-CD3 plus anti-CD28 did express TSLPR. After T-cell receptor stimulation, TSLP directly enhanced the expansion of activated CD8(+) T cells. Interestingly, using monocyte-derived DCs pulsed with a cytomegalovirus (CMV)-specific pp65 peptide, we found that although interleukin-2 allowed expansion of both CMV-specific and non-specific CD8(+) T cells, TSLP induced expansion of only CMV-specific CD8(+) T cells. These results suggest that human TSLP directly enhances expansion of CD8(+) T cells and that the direct and indirect action of TSLP on expansion of target antigen-specific CD8(+) T cells may be beneficial to adoptive cell transfer immunotherapy.

Estimation of the detection probability for Yangtze finless porpoises (Neophocaena phocaenoides asiaeorientalis) with a passive acoustic method.

Yangtze finless porpoises were surveyed by using simultaneous visual and acoustical methods from 6 November to 13 December 2006. Two research vessels towed stereo acoustic data loggers, which were used to store the intensity and sound source direction of the high frequency sonar signals produced by finless porpoises at detection ranges up to 300 m on each side of the vessel. Simple stereo beam forming allowed the separation of distinct biosonar sound source, which enabled us to count the number of vocalizing porpoises. Acoustically, 204 porpoises were detected from one vessel and 199 from the other vessel in the same section of the Yangtze River. Visually, 163 and 162 porpoises were detected from two vessels within 300 m of the vessel track. The calculated detection probability using acoustic method was approximately twice that for visual detection for each vessel. The difference in detection probabilities between the two methods was caused by the large number of single individuals that were missed by visual observers. However, the sizes of large groups were underestimated by using the acoustic methods. Acoustic and visual observations complemented each other in the accurate detection of porpoises. The use of simple, relatively inexpensive acoustic monitoring systems should enhance population surveys of free-ranging, echolocating odontocetes.

Psychosis proneness, coping, and perceptions of social support.

The current study examined coping styles and perceived levels of social support in hypothetically psychosis-prone individuals. Results suggest that psychosis-prone individuals did not differ from a comparison group on levels of adaptive coping or positive social support but that they did endorse higher rates of nonadaptive coping and negative social support compared with the comparison group.

Modulations of glucocorticoid-induced apoptosis linked to the p53 deletion and to the apoptosis susceptibility gene Rapop1 (Radiation-induced apoptosis 1).

We have analysed the effects of p53 and of the apoptosis susceptibility gene Rapop1 (Radiation-induced apoptosis 1) located on chromosome 16 on glucocorticoid- and radiation-induced in vivo apoptosis of thymocytes. For those analyses, we used Rapop1 semicongenic mice heterozygous for the STS and BALB/cHeA alleles in the chromosomal segment containing Rapop1 in the BALB/cHeA background, mice bearing a p53 deficient allele in the BALB/cHeA background and the genetic crosses between these mice. The p53 wild type mice with a STS/A allele at the Rapop1 locus were less susceptible to both radiation- and glucocorticoid-induced apoptosis than those with homozygous BALB/cHeA alleles at this locus. Surprisingly, glucocorticoid-induced apoptosis was enhanced in the p53 hemizygous mice and considerably increased in the p53 nullizygous mice. In contrast, a sizable reduction of radiation-induced apoptosis was seen in the p53 hemizygous mice. The low susceptiblity to glucocortocoid-induced apoptosis linked to the STS allele of Rapop1 was less pronounced in the p53 hemizygous mice and a diminished effect of Rapop1 on radiation-induced apoptosis was seen in these mice. Although it remains to be established whether the genes modulating glucocortocoid-induced apoptosis are identical to p53 and Rapop1, our data suggest that p53 and Rapop1 may participate in glucocorticoid-induced apoptosis of thymocytes.

Evaluation of the antimicrobial activity and materials compatibility of orthophthalaldehyde as a high-level disinfectant.

We tested the antimicrobial activity of orthophthalaldehyde (OPA) against 21 strains (16 species) of pathogenic microorganisms that cause hospital-associated infections. Changes in hepatitis B surface antigen (HBs-Ag) resulting from the addition of OPA to HBs-Ag-positive serum were measured using a radioimmunoassay. We also examined the effect of immersing medical instruments in OPA (0.55%) for 168 h at room temperature. OPA (0.5%, 0.37% and 0.25%) killed 11 strains of vegetative bacteria within 15 s, and it killed the test micro-organisms faster than 3.0% glutaraldehyde (GTA). Incubation with OPA or GTA caused levels of HBs-Ag to fall below a cut-off value within 30 s. OPA did not adversely affect instruments made from various materials. OPA demonstrated more effective antimicrobial activity than GTA against a range of microorganisms. We conclude that OPA should replace GTA as the first-choice high-level disinfectant for endoscopes, considering its antimicrobial efficacy and low inhalation toxicity.

Distribution of the Kexin family proteases in pancreatic islets: PACE4C is specifically expressed in B cells of pancreatic islets.

The distribution of Kexin family proteases in adult rat pancreatic islets was investigated by immunohistochemical means using a series of specific antibodies specific for PC1, PC2, PC6, Furin, PACE4A and a recently identified member of the Kexin family, PACE4C. PACE4C expression was limited to B cells of the pancreatic islets. PC2 was found in A and in some D cells more than in B cells and PC1 was evident only in B cells. Furin and PC6 were weakly and evenly expressed in the entire islet. PACE4A was hardly found in the islets. These findings indicated that individual Kexin family proteases are uniquely distributed in the islets and suggested that these proteases share roles in these cells as follows: PC2 is involved in the peptide hormone precursor processing in A cells and in D cells, and PACE4C, PC1 and PC2 (mainly PACE4C and PC1) are responsible for the processing event(s) specific to B cells.

Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle.

BACKGROUND: The fact that most women experience sleep changes across the menstrual cycle is thought to be associated with changes in circadian rhythms; however, few studies have investigated this relationship. METHODS: We applied an ultrashort sleep-wake schedule to eight healthy women and studied diurnal fluctuations in sleep propensity, sleepiness, rectal temperature, and serum concentrations of melatonin, thyroid-stimulating hormone, and cortisol in the follicular and luteal phases. RESULTS: In the luteal phase, amplitude of core body temperature, total melatonin secretions, and amplitudes of TSH and cortisol rhythms were significantly decreased, whereas sleepiness and occurrence of slow-wave sleep during the daytime were significantly increased. Differences in the amount of daytime slow-wave sleep across the menstrual cycle were positively correlated with differences in the daily mean rectal temperature. CONCLUSIONS: The findings suggest that the amplitude of circadian oscillation may be dampened in the luteal phase. Increased daytime sleepiness in the luteal phase may be associated with increased daytime slow-wave sleep, due possibly to changes in thermoregulation in the luteal phase.

Cardiovascular effects of total hip placement in man. With observations on the effects of methylmethacrylate on the isolated rabbit heart.

The cardiovascular effects of total hip placement were evaluated in 10 surgical patients, aged 55 to 82, while receiving fluroxene-N2O-O2 anesthesia. The anesthetic regimen caused mild cardiovascular depression. The placement of the acrylic cement into the acetabulum and femoral shaft also induced mild cardiovascular depression, but these changes were not significant at p less than 0.05. In one 67-yr-old woman, there were significant reductions of cardiac output and stroke volume 2 min after the insertion of acrylic into the femoral shaft, despite careful replacement of intravascular loss and careful anesthetic management. Methylmethacrylate (1 X 10(-6) to 1 X 10(-4), v/v) was administered to 24 isolated perfused rabbits hearts. These concentrations of methylmetacrylate are of the same order as measurable blood levels in surgical patients. There was a dose-dependent depression of left ventricular dP/dt correlated with a depression of the spontaneous heart rate. When the bradycardia was prevented by electrically pacing the hearts or the administration of atropine, the depressed dP/dt rose to control levels. Reduction in myocardial temperature and heart rate by means of reduction in perfusate temperature of the isolated hearts reduced the myocardial depressant effect of methylmethacrylate.

Effect of soymilk consumption on serum estrogen and androgen concentrations in Japanese men.

Soy consumption has been associated with a reduced risk of prostate cancer. The mechanism for this association may involve the effect of soy on the endocrine system. We conducted a randomized dietary intervention study to determine the effects of soy consumption on serum levels of steroid hormones in men. Thirty-five men were randomly assigned to either a soymilk-supplemented group or a control group. The men in the soy-supplemented group were asked to consume 400 ml of soymilk daily for 8 weeks. The men in the control group maintained their usual diet. Blood samples were obtained just before the initiation of the dietary period and thereafter every two weeks for 12 weeks. Changes in hormone concentrations were analyzed and compared between the two groups using the mixed linear regression model against weeks from the start of the dietary period. The mean (SD) soymilk intake estimated from dietary records during the dietary study period was 342.9 (SD, 74.2) ml in the soymilk-supplemented group. There was a significant difference between the two groups in terms of changes in serum estrone concentrations, which tended to decrease in the soy-supplemented group and increase in the control group over time. None of the other hormones measured (estradiol, total and free-testosterone, or sex hormone-binding globulin) showed any statistical difference between the two groups in terms of patterns of change. The results of the study indicate that soymilk consumption may modify circulating estrone concentrations in men.

Histochemical reactivity of normal, metaplastic, and neoplastic tissues to alpha-linked N-acetylglucosamine residue-specific monoclonal antibody HIK1083.

Monoclonal antibody (MAb) HIK1083, which is obtained by immunizing mice with a preparation of rat gastric mucins, has been shown to bind specifically to alpha-linked N-acetylglucosamine (alpha-GlcNAc). We investigated the specificity of MAb HIK1083 by immunostaining normal human organs, mucinous metaplasia of human pancreas, adenocarcinomas of human stomach, pancreas, and colon, and normal rat organs. The specificity was investigated by making comparisons with (a) a stain that labels Class III concanavalin A (ConA)-reactive mucin (Class III mucin), i.e., paradoxical ConA (PCS), and (b) staining with horseradish peroxidase (HRP)-conjugated Griffonia simplicifolia agglutinin II (GSA-II). In normal human and rat organs and in mucinous metaplasia of human pancreas, immunostaining with MAb HIK1083 and PCS showed similar specificities for mucins in glandular mucous cells. In adenocarcinoma of stomach and pancreas, GSA-II showed the most widespread positivity, PCS showed the least, and MAb HIK1083 showed a reactivity between those two extremes. Colon adenocarcinomas were labeled only with GSA-II. These results demonstrate that MAb HIK1083 could be a useful screening tool for Class III mucin in normal, metaplastic, and carcinoma tissues, and that the alpha-GlcNAc residue is one of the specific sugar residues found in Class III mucin.

Inhibition of Helicobacter pylori-induced cyclo-oxygenase-2 aggravates NSAID-caused gastric damage in Mongolian gerbils.

BACKGROUND: The effect of Helicobacter pylori infection on non-steroidal anti-inflammatory drug-induced gastric mucosal injury is controversial. AIM: To examine the effect of the interaction between H. pylori and non-steroidal anti-inflammatory drugs on gastric mucosal injury. METHODS: Mongolian gerbils infected with H. pylori were treated with indometacin at 8 mg/kg for 2 days or 7 days. Mucosal damage was assessed by macroscopic and histological examination, and myeloperoxidase activity was measured as an index of neutrophil infiltration. The expression levels of cyclo-oxygenase proteins were determined by Western blot analysis and cyclo-oxygenase activity. RESULTS: A 2-day course of indometacin did not cause an increase in gastric damage in H. pylori-infected Mongolian gerbils compared to uninfected gerbils, while a 7-day course of indometacin caused additive gastric damage in H. pylori-infected animals. H. pylori infection induced cyclo-oxygenase-2 expression in the stomach. Treatment with indometacin for 2 days did not significantly affect cyclo-oxygenase activity in H. pylori-infected animals, while treatment for 7 days inhibited both cyclo-oxygenase-1 and cyclo-oxygenase-2 activities. Pre-treatment with a selective cyclo-oxygenase-2 inhibitor aggravated mucosal injury in H. pylori-infected animals treated or not treated with indometacin for 2 days. CONCLUSIONS: Our results suggest that cyclo-oxygenase-2 protein induced by H. pylori infection may be involved in the defence of the gastric mucosa against damage caused by non-steroidal anti-inflammatory drugs. Therefore, inhibition of cyclo-oxygenase-2 activity may enhance non-steroidal anti-inflammatory drug-caused gastric damage in H. pylori-infected animals.

Induction of cyclooxygenase-2 in mesothelial cells in peritonitis caused by perforated ulcers--an immunohistochemical study in humans.

BACKGROUND: Increasing evidence suggests that mesothelial cells contribute to the control of inflammation in the peritoneal cavity by secreting prostaglandins. A study has shown that cyclooxygenase (COX)-2 knockout mice die partly as a result of peritonitis. AIM: To investigate the expression and location of COX in peritonitis associated with peptic ulcer perforation. METHODS: Gastric and duodenal tissues were collected intraoperatively from nine and four patients, respectively, and immunohistochemical staining for COX-1 and COX-2 was performed. RESULTS: Histologically, all patients had severe peritonitis around the perforation sites, into which many inflammatory cells and fibroblasts had infiltrated, and reactive mesothelial cells exhibited hyperplastic change. The COX-1 protein was not detected, whereas COX-2 was abundant in reactive mesothelial cells near the perforation site and disappeared away from the site. Macrophages and fibroblasts around the perforation site also revealed immunostaining for COX-2. CONCLUSIONS: Our results showed that COX-2 protein is induced in mesothelial cells, as well as in macrophages and fibroblasts, in inflamed peritoneal tissues associated with peptic ulcer perforation, suggesting involvement of COX-2 in tissue repair.

Mucin histochemistry of pancreatic duct cell carcinoma, with special reference to organoid differentiation simulating gastric pyloric mucosa.

The present study was undertaken to explore mucins produced in normal, metaplastic, and hyperplastic ductal epithelia as well as in carcinoma tissues of the pancreas, and used a battery of histochemical techniques. Thirty-five cases of ordinary pancreatic duct cell carcinoma and nine cases of duct cell carcinoma, which fulfilled the clinical criteria of "mucin-producing carcinoma of the pancreas," were examined. The results indicated that all lesions of mucinous metaplasia with or without papillary hyperplasia as well as atypical hyperplasia characteristically had gastric mucins and showed organoid differentiation simulating the gastric pyloric mucosa, but never stained for 8-O-acetyl-N-acetylneuraminic acid, which is a histochemical marker of the large intestine. Ordinary duct cell carcinoma also contained gastric mucins and small intestinal mucins and showed organoid differentiation, but rarely had 8-O-acetyl-N-acetylneuraminic acid. Mucin-producing carcinomas were classified into two groups: the ordinary duct cell carcinoma group and a group that showed marked atrophy and extensive fibrosis of the parenchyma, a lack of organoid differentiation and gastric mucins, and an abundance of large and small intestinal mucins. These results suggest that gastrointestinal mucins are useful markers to detect cancer-related lesions and cancers of the pancreas.