A high α1-antitrypsin/interleukin-10 ratio predicts bacterial pneumonia in adults with community-acquired pneumonia: a prospective cohort study.

BACKGROUND: Current microbiological tests fail to identify the causative microorganism in more than half of all pneumonia cases. We explored biomarkers that could be used for differentiating between bacterial and viral pneumonia in patients with community-acquired pneumonia (CAP). METHODS: In this prospective cohort study conducted in Japan, data obtained from adult patients with bacterial pneumonia, including bacterial and viral coinfections (bacterial pneumonia [BP] group), and purely viral pneumonia (VP group) at diagnosis were analyzed using multivariate logistic regression analysis to identify predictors of bacterial pneumonia. Furthermore, a decision tree was developed using the predictors. RESULTS: A total of 210 patients were analyzed. The BP and VP groups comprised 108 and 18 patients, respectively. The other 84 patients had no identified causative microorganism. The two groups shared similar characteristics, including disease severity; however, a significant difference (p < 0.05) was observed between the two groups regarding sputum type; sputum volume score; neutrophil counts; and serum levels of interleukin (IL)-8, IL-10, and α1-antitrypsin (AAT). Sputum volume score (p < 0.001), IL-10 (p < 0.001), and AAT (p = 0.008) were ultimately identified as predictors of BP. The area under the curve for these three variables on the receiver operating characteristic (ROC) curve was 0.927 (95% confidence interval [CI]: 0.881-0.974). The ROC curve for sputum volume score and an AAT/IL-10 ratio showed a diagnostic cutoff of 1 + and 65, respectively. Logistic regression analysis using dichotomized variables at the cutoff values showed that the odds ratios for the diagnosis of BP were 10.4 (95% CI: 2.2-50.2) for sputum volume score (absence vs. presence) and 19.8 (95% CI: 4.7-83.2) for AAT/IL-10 ratio (< 65 vs. ≥ 65). CONCLUSIONS: Considering that obtaining a definitive etiologic diagnosis with the current testing methods is difficult and time consuming, a decision tree with two predictors, namely sputum volume and the AAT/IL-10 ratio, can be useful in predicting BP among patients diagnosed with CAP and facilitating the appropriate use of antibiotics. TRIAL REGISTRATION: UMIN000034673 registered on November 29, 2018.

A case series of histoplasmosis patients with elevated serum soluble interleukin-2 receptor levels.

Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but rarely in Japan. In recent years, however, the number of histoplasmosis patients in Japan has increased. In addition, to our knowledge, there are no previous reports of increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with histoplasmosis. We report a case series of histoplasmosis in three Japanese temporary workers in Manzanillo, Mexico. All three patients developed a persistent high fever and general fatigue. Laboratory tests showed increased C-reactive protein levels and mild liver dysfunction. All patients also showed increased soluble interleukin-2 receptor (sIL-2R) levels. Chest computed tomography revealed multiple nodules in both lung fields. All patients were positive for serum anti-Histoplasma antibodies, and two patients were positive for Histoplasma on polymerase chain reaction tests. After treatment that included antifungals, their conditions gradually improved and laboratory data normalized. Although one patient developed respiratory failure, this patient recovered with antifungal therapy in combination with methylprednisolone. Serum sIL-2R levels in all patients gradually declined to normal levels, indicating their recovery from Histoplasma infection. From our experience with these patients, sIL-2R levels may be a useful biomarker for patients with histoplasmosis.

DEspR roles in tumor vasculo-angiogenesis, invasiveness, CSC-survival and anoikis resistance: a 'common receptor coordinator' paradigm.

A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.

Distinct QTLs cosegregate with worse hypertension and renal disease in ovariectomized F2[Dahl S × R]-intercross rats.

OBJECTIVES: Salt-sensitive hypertension is highly prevalent in postmenopausal women, with approximately 75% of postmenopausal women found to be hypertensive in the US. Insight from surgical menopause (ovariectomized) patients directly links the loss of endogenous estrogens to salt-sensitive hypertension in previously healthy, salt-resistant women. However, controversial benefit of hormone replacement therapy in postmenopausal women raises the hypothesis that the loss of endogenous estrogens alters genetic susceptibility determinants per se, resulting in hypertension mechanisms beyond correction by hormone replacement. METHODS: We studied ovariectomy-induced changes in hypertension phenotypes and performed a total genome scan for genetic determinants or quantitative trait loci (QTLs), which cosegregate with salt-sensitive hypertension and/or target organ complications in ovariectomized 6-month-old F2[Dahl S × R]-intercross female rats. We used SBP, glomerular injury score (GIS) and relative heart weight (RHW) as quantitative traits. We compared QTLs between ovariectomized and nonovariectomized F2[Dahl S × R]-intercross rats using identical phenotype and genotype characterization. RESULTS: Ovariectomy worsened hypertension and hypertensive nephrosclerosis but reduced RHW. Although some QTLs are common, hence ovarian hormone-independent, distinct BP-QTLs (on chromosomes 9, 13, 20 and X), RHW-QTLs (on chromosomes 1 and 3) and GIS-QTLs (on chromosomes 1 and 8) were detected in ovariectomized F2[Dahl S × R]-intercross female rats. CONCLUSION: Detection of worse hypertension phenotype and distinct QTLs in ovariectomized F2[Dahl S × R]-intercross female rats suggest that distinct genetic determinants underlie postmenopausal hypertension, which are activated, or de-repressed, upon the loss of estrogens.

Effect of acupuncture on salivary immunoglobulin A after a bout of intense exercise.

UNLABELLED: In the field of athletics, acupuncture has been used for treatment of injury, reduction of fatigue and management of physical condition. However, there is little information on the effect of acupuncture on the immune function in response to exercise. PURPOSE: The aim of this study was to examine the effect of acupuncture treatment on the mucosal immune function after a single period of intense exercise by measuring salivary immunoglobulin A (SIgA). METHODS: 12 healthy men (23.6+/-SEv 0.3 years) participated in this study with a crossover design. The subjects exercised on a bicycle equipped with an ergometer at 75% VO(2)max for 60 min. Acupuncture treatment was applied at LU6, LI4, ST36 and ST6, for 30 min after the exercise. The control treatment was rest without acupuncture and that the order of the treatment was randomised. We measured parameters including saliva flow rate, SIgA concentration, SIgA secretion rate, heart rate and plasma catecholamine concentration all before the exercise and at 1 h, 2 h, 3 h, 4 h and 24 h after the exercise. The visual analogue scale for self-perceived tiredness and the profile of mood states questionnaires were recorded before the exercise and at 24 h after the exercise. RESULT: Intense exercise-induced decrease of SIgA levels was attenuated by the acupuncture treatment. In contrast, the subjective fatigue score and psychological measurement were not affected by the acupuncture. CONCLUSION: Acupuncture treatment may attenuate the decrease in SIgA level induced by intense exercise.

Exercise-induced oxidative DNA damage and lymphocytopenia in sedentary young males.

UNLABELLED: Post high-intensity exercise lymphocytopenia is well documented, but its underlying mechanisms have not been fully elucidated. A possible mechanism is a reactive oxygen species-induced DNA damage after high-intensity exercise. Furthermore, lymphocyte apoptosis related to DNA damage might contribute to exercise-induced lymphocytopenia. PURPOSE: This study examined lymphocytopenia, lymphocyte oxidative DNA damage, and apoptosis in young healthy sedentary males after acute high-intensity exercise. METHOD: Fifteen subjects exercised on bicycle ergometers for 1 h at 75% of their VO2max. Venous blood samples were taken before exercise (PRE) and hourly after exercise until 4 h (P0-P4). Lymphocyte counts, oxidative DNA damage evaluated using the Comet assay with human 8-oxoguanine DNA glycosylase, and serum lipid peroxide (LPO) concentration were measured. Furthermore, lymphocyte superoxide, Fas receptor (CD95), and Annexin-V-positive lymphocyte apoptosis cells were measured in 10 subjects who exercised and gave blood samples as described above. RESULTS: Lymphocyte counts became significantly lower than the PRE value (P < 0.05): 20.4% at P1, 24.3% at P2, and 16.3% at P3. Moreover, LPO significantly increased by P2 (P < 0.05): 1.6-fold. The % DNA in tail, indicating oxidative DNA damage, was significantly higher at P3 (54.3 +/- 12.8%) than at PRE (42.6 +/- 11.1%, P < 0.05). The lymphocyte superoxide level was significantly higher (51.3%) than the PRE value (P < 0.05). Neither CD95 nor Annexin-V-positive cells were significantly different than the PRE value. CONCLUSION: Results of this study suggest that lymphocyte oxidative DNA damage can relate to lymphocytopenia, although DNA damage was not associated with apoptosis in healthy young sedentary males.

Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats.

Sex-specific differences in polygenic (essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating sex-common disease mechanisms in premenopausal women. However, emerging observations indicate sex-specific genetic susceptibility in various traits, thus requiring systematic study. Here we report a comparative analysis of independent total genome scans for salt-sensitive hypertension susceptibility quantitative trait loci (QTLs) in male and female F2 [Dahl R/jrHS x S/jrHS] intercross rats exposed to high-salt (8% NaCl) rat diets. Hypertension was phenotyped with three quantitative traits: blood pressure (BP) elevation associated with increased hypertensive renal disease [glomerular injury score (GIS)] and increased cardiac mass [relative heart weight (RHW)] obtained 8-12 wk after high-salt challenge; 24-h nonstress, telemetric BP measurements were used. Although sex-common QTLs were detected for BP [chromosome (chr) 1-144.3 Mbp; chr 1-208.8 Mbp], GIS (chr 1-208.8 Mbp), and cardiac mass (chr 5-150.3 Mbp), most QTLs across the three phenotypes studied are gender specific as follows: female QTLs for BP (chr 2-106.7 Mbp, chr 2-181.7 Mbp, chr 5-113.9 Mbp, chr 5-146.7 Mbp, chr 12-12.8 Mbp), GIS (chr 15-59.6 Mbp), and RHW (chr 2-31.5 Mbp, chr 5-154.7 Mbp, chr 5-110.9 Mbp); male QTLs for BP (chr 2-196.7 Mbp, chr 11-48.0 Mbp, chr 20-35.7 Mbp), GIS (chr 6-3.3 Mbp, chr 20-40.7 Mbp), and RHW (chr 6-3.3 Mbp, chr 20-40.7 Mbp). Furthermore, interacting loci with significant linkage were detected only in female F2 intercross rats for BP and hypertensive renal disease. Comparative analyses revealed concordance of BP QTL peaks with previously reported rat model and human hypertension susceptibility genes and with BP QTLs in previous Dahl S-derived F2 intercross studies and also suggest strain-specific genetic modifiers of sex-specific determinants. Altogether, the data provide key experimental bases for sex-specific investigation of mechanisms and intervention and prevention strategies for polygenic hypertension in humans.

Intrapulmonary pharmacokinetics of telithromycin, a new ketolide, in healthy Japanese volunteers.

The concentrations of telithromycin, a new ketolide antimicrobial agent, in alveolar macrophages (AMs) and bronchoalveolar epithelial lining fluid (ELF) were determined in order to investigate the transfer of the drug into target tissue, relative to plasma, following multiple oral doses of telithromycin. Twenty-four healthy male Japanese volunteers were randomly allocated to four groups. Each subject was given 600 or 800 mg of telithromycin once daily for 5 days, followed by bronchoalveolar lavage (BAL) 2 or 8 h after the last dose (group A and B: 600 mg, 2 and 8 h BAL time point; group C and D: 800 mg, 2 and 8 h BAL time point). The mean concentrations of the drug in AMs and ELF were 34.54 and 4.92 mg/liter in group A, 50.97 and 2.26 mg/liter in group B, 25.47 and 4.24 mg/liter in group C, and 108.22 and 4.31 mg/liter in group D, respectively, which markedly exceeded concentrations in plasma. These results demonstrated good transfer of telithromycin into AMs and ELF, suggesting good efficacy against common respiratory pathogens, including intracellular pathogens and atypical microorganisms.