Prostaglandin E2 Inhibits Histamine-Evoked Ca2+ Release in Human Aortic Smooth Muscle Cells through Hyperactive cAMP Signaling Junctions and Protein Kinase A.
In human aortic smooth muscle cells, prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca2+ concentration evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca2+ signals by PGE2 Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3 The rate of Ca2+ removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca2+ signals by PGE2 or butaprost (to activate EP2 receptors selectively), but it modestly attenuated responses to EP4 receptors, activation of which generated less cAMP than EP2 receptors. We conclude that inhibition of histamine-evoked Ca2+ signals by PGE2 occurs through "hyperactive signaling junctions," wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H1 receptors from phospholipase C. This sequence allows digital signaling from PGE2 receptors, through cAMP and PKA, to histamine-evoked Ca2+ signals.


Water quality failures in distribution networks-risk analysis using fuzzy logic and evidential reasoning.
The evaluation of the risk of water quality failures in a distribution network is a challenging task given that much of the available data are highly uncertain and vague, and many of the mechanisms are not fully understood. Consequently, a systematic approach is required to handle quantitative-qualitative data as well as a means to update existing information when new knowledge and data become available. Five general pathways (mechanisms) through which a water quality failure can occur in the distribution network are identified in this article. These include contaminant intrusion, leaching and corrosion, biofilm formation and microbial regrowth, permeation, and water treatment breakthrough (including disinfection byproducts formation). The proposed methodology is demonstrated using a simplified example for water quality failures in a distribution network. This article builds upon the previous developments of aggregative risk analysis approach. Each basic risk item in a hierarchical framework is expressed by a triangular fuzzy number, which is derived from the composition of the likelihood of a failure event and the associated failure consequence. An analytic hierarchy process is used to estimate weights required for grouping noncommensurate risk sources. The evidential reasoning is proposed to incorporate newly arrived data for the updating of existing risk estimates. The exponential ordered weighted averaging operators are used for defuzzification to incorporate attitudinal dimension for risk management. It is envisaged that the proposed approach could serve as a basis to benchmark acceptable risks in water distribution networks.


DISEASES: text mining and data integration of disease-gene associations.
Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases. The DISEASES resource is accessible through a web interface at http://diseases.jensenlab.org/, where the text-mining software and all associations are also freely available for download.


A Monte Carlo dose calculation tool for radiotherapy treatment planning.
A Monte Carlo user code, MCDOSE, has been developed for radiotherapy treatment planning (RTP) dose calculations. MCDOSE is designed as a dose calculation module suitable for adaptation to host RTP systems. MCDOSE can be used for both conventional photon/electron beam calculation and intensity modulated radiotherapy (IMRT) treatment planning. MCDOSE uses a multiple-source model to reconstruct the treatment beam phase space. Based on Monte Carlo simulated or measured beam data acquired during commissioning, source-model parameters are adjusted through an automated procedure. Beam modifiers such as jaws, physical and dynamic wedges, compensators, blocks, electron cut-outs and bolus are simulated by MCDOSE together with a 3D rectilinear patient geometry model built from CT data. Dose distributions calculated using MCDOSE agreed well with those calculated by the EGS4/DOSXYZ code using different beam set-ups and beam modifiers. Heterogeneity correction factors for layered-lung or layered-bone phantoms as calculated by both codes were consistent with measured data to within 1%. The effect of energy cut-offs for particle transport was investigated. Variance reduction techniques were implemented in MCDOSE to achieve a speedup factor of 10-30 compared to DOSXYZ.


Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study.
Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. We evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. At enrolment (1993-1997), spouses provided information about ever use of specific pesticides, including 10 OPs, demographic information, reproductive health history and other potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% CIs for all cancers diagnosed through 2010 for North Carolina and through 2011 for Iowa. Among 30,003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43). We observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation.


The sensory somatotopic map of the human hand demonstrated at 4 Tesla.
Recent attempts at high-resolution sensory-stimulated fMRI performed at 1.5 T have had very limited success at demonstrating a somatotopic organization for individual digits. Our purpose was to determine if functional MRI at 4 T can demonstrate the sensory somatotopic map of the human hand. Sensory functional MRI was performed at 4 T in five normal volunteers using a low-frequency vibratory stimulus on the pad of each finger of the left hand. A simple motor control task was also performed. The data were normalized to a standard atlas, and individual and group statistical parametric maps (SPMs) were computed for each task. Volume of activation and distribution of cluster maxima were compared for each task. For three of the subjects, the SPMs demonstrated a somatotopic organization of the sensory cortex. The group SPMs demonstrated a clear somatotopic organization of the sensory cortex. The thumb to fifth finger were organized, in general, with a lateral to medial, inferior to superior, and anterior to posterior relationship. There was overlap in the individual SPMs between fingers. The sensory activation spanned a space of 12-18 mm (thumb to fifth finger) on the primary sensory cortex. The motor activation occurred consistently at the superior-most extent of the sensory activation within and across subjects. The sensory somatotopic map of the human hand can be identified at 4 T. High-resolution imaging at 4 T can be useful for detailed functional imaging studies.


A novel in vivo skin extensibility test for joint hypermobility.
The stress/strain curve derived from stretching skin is not linear, but follows a J-shaped curve. An initial generous yield is followed by a steep linear phase where considerable additional force is required to achieve modest increases in deformation. The former represents the taking up of slack resulting from the alignment of dermal collagen bundles in the line of force, while the gradient of the latter represents Young's modulus for skin. Skin hyperextensibility in Ehlers-Danlos syndrome (EDS) is limited to the initial phase of taking up slack. Skin hyperextensibility and joint hypermobility (JHM) form part of the Revised 1998 Brighton diagnostic criteria for the benign joint hypermobility syndrome (BJHS), considered by many to be akin to EDS-hypermobility type. JHM may be screened for using the Beighton Score or a 5-point questionnaire. Our aim was to validate a novel method of measuring skin extensibility based on these observations in addition to revalidating the 5-point questionnaire. 250 volunteers (131 female), median age 39 years (range 18-89 yrs), without BJHS, had their joint mobility evaluated using the Beighton Score, compared to the 5-point questionnaire. A Beighton score > or = 4/9 was considered to represent JHM. Skin extensibility was determined by placing 2 dots on the dorsum of the right hand between the second and third metacarpals, approximately 10 mm apart, and was measured using an electronic caliper. Perpendicular to the metacarpals, a force was applied until the skin was fully taut and the increment was measured. Skin-fold thickness was measured using a Harpenden caliper. A corrected skin extensibility score (CSES) was calculated by dividing the percentage increment by skin thickness. Interobserver variability was measured in a further 50 healthy volunteers. The prevalence of JHM was 17.6%. Revalidation of the 5-point questionnaire returned a sensitivity of 0.85 and specificity of 0.85. The mean CSES was 23.84%/mm in the hypermobile group versus 13.55%/mm in the normal mobility group (p < 0.0001). CSES sensitivity was 0.72, specificity 0.75. The kappa value for interobserver variability was 0.83. The CSES is a useful and reproducible measure of skin extensibility in health. Further work is warranted to validate this test in patients with BJHS.


Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacologic features of human tumors.
Myxoid liposarcoma is a common subtype of liposarcoma. It is associated in more than 90% of cases with the chromosomal translocation t(12;16)(q13;p11) leading to the fusion FUS-CHOP gene that is responsible for the oncogenic transformation of preadipocytes. Recently the marine natural product trabectedin has shown highly selective activity for myxoid liposarcoma, even in the most aggressive round-cell subtype. Fragments of 17 sarcomas were transplanted s.c. in female athymic NCr-nu/nu mice. Xenografts were established and characterized by morphology, fluorescence in situ hybridization analysis for the translocation and reverse transcriptase-PCR analysis for fusion transcripts. Trabectedin was injected i.v. Seven of 17 tumors grew as continuous xenografts, five of them being myxoid liposarcoma of the round-cell subtype. The chromosomal rearrangement and fusion transcripts in different passages were the same as in the human tumors from which they were derived. The responsiveness to trabectedin in type II myxoid liposarcoma xenografts was as high as in patients. The pathologic response was associated with the presence of the FUS-CHOP fusion gene, indicating that the drug does not totally eradicate the disease. Type III myxoid liposarcoma xenografts seemed much less sensitive to trabectedin, confirming previous clinical observations. This study reports for the first time the characterization of human myxoid liposarcoma xenografts that adequately mimic the biological and pharmacologic features of the human tumor. These models offer a useful tool for investigating the mechanism of selectivity of trabectedin, testing new combinations with this drug and evaluating novel therapies for myxoid liposarcoma.


Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.
Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both. In this multicentre, phase 3, randomised, controlled trial, we enrolled patients aged 18 years or older from 129 UK centres who had histologically confirmed node-positive or high-risk node-negative operable breast cancer, had undergone complete excision, and were due to receive adjuvant chemotherapy. Patients were randomly assigned to receive four cycles of 100 mg/m2 epirubicin either every 3 weeks (standard epirubicin) or every 2 weeks with 6 mg pegfilgrastim on day 2 of each cycle (accelerated epirubicin), followed by four 4-week cycles of either classic cyclophosphamide, methotrexate, and fluorouracil (CMF; 600 mg/m2 cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1-14; 40 mg/m2 methotrexate intravenously on days 1 and 8; and 600 mg/m2 fluorouracil intravenously on days 1 and 8 of each cycle) or four 3-week cycles of 2500 mg/m2 capecitabine (1250 mg/m2 given twice daily on days 1-14 of each cycle). The randomisation schedule was computer generated in random permuted blocks, stratified by centre, number of nodes involved (none vs one to three vs four or more), age (≤50 years vs >50 years), and planned endocrine treatment (yes vs no). The primary endpoint was TTR, defined as time from randomisation to first invasive relapse or breast cancer death, with intention-to-treat analysis of standard versus accelerated epirubicin and per-protocol analysis of CMF versus capecitabine. This trial is registered with ISRCTN, number 68068041, and with ClinicalTrials.gov, number NCT00301925. From Dec 16, 2005, to Dec 5, 2008, 4391 patients (4371 women and 20 men) were recruited. At a median follow-up of 85·6 months (IQR 80·6-95·9) no significant difference was seen in the proportions of patients free from TTR events between the accelerated and standard epirubicin groups (overall hazard ratio [HR] 0·94, 95% CI 0·81-1·09; stratified p=0·42). At 5 years, 85·9% (95% CI 84·3-87·3) of patients receiving standard epirubicin and 87·1% (85·6-88·4) of those receiving accelerated epirubicin were free from TTR events. 4358 patients were included in the per-protocol analysis, and no difference was seen in the proportions of patients free from TTR events between the CMF and capecitabine groups (HR 0·98, 95% CI 0·85-1.14; stratified p=0·00092 for non-inferiority). Compared with baseline, significantly more patients taking CMF than those taking capecitabine had clinically relevant worsening of quality of life at end of treatment (255 [58%] of 441 vs 235 [50%] of 475; p=0·011) and at 12 months (114 [34%] of 334 vs 89 [22%] of 401; p<0·001 at 12 months) and had worse quality of life over time (p<0·0001). Detailed toxicity and quality-of-life data were collected from 2115 (48%) of treated patients. The most common grade 3 or higher adverse events in cycles 1-4 were neutropenia (175 [16%]) and fatigue (56 [5%]) of the 1070 patients treated with standard epirubicin, and fatigue (63 [6%]) and infection (34 [3%]) of the 1045 patients treated with accelerated epirubicin. In cycles 5-8, the most common grade 3 or higher adverse events were neutropenia (321 [31%]) and fatigue (109 [11%]) in the patients treated with CMF, and hand-foot syndrome (129 [12%]) and diarrhoea (67 [6%]) in the 1044 patients treated with capcitabine. We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life. Cancer Research UK, Amgen, Pfizer, and Roche.


[Factors associated with acceptance of postpartum tubal ligation among HIV-infected women].
To identify the factors associated with the acceptance of tubal ligation after childbirth among HIV-infected patients. A case-control study was conducted from March 1988 to February 1999, at Mexico's National Institute of Perinatology (INPer), in 72 HIV-positive pregnant women. Cases were 49 women who accepted postpartum tubal ligation after childbirth, and controls were 23 women who refused this birth control method. Data collected for each patient were demographic characteristics, sexual and reproductive history, and HIV status. Statistical analysis consisted of descriptive measures, Chi 2 or Fisher's exact test for categorical variables, and Student's t test for continuous variables. Odds ratios (OR) with 95% CI were used to compare groups and potential confounders were assessed by stratified analysis with the Mantel-Haenszel method. The patients' mean age was 25.5 +/- 5.5 years. The median gestation period was 27 weeks (range 7 to 40 weeks); 16 women (22.2%) had no prenatal care visits at INPer. The median time of HIV positivist awareness was 9 months (range 1 to 108). Variables associated with acceptance of tubal ligation were: having a prior childbirth (OR 11.1, 95% CI 3.4 to 36), pregnancy care from 1995 onward (OR 4.7, 95% CI 1.7 to 13.3), and having given birth to an HIV-infected child (OR 4.6, 95% CI 1.05 to 23.1). Stratified analysis showed no modification of the strength of association of these variables with acceptance of tubal ligation. A prior childbirth was the most important predictor of tubal ligation acceptance. The English version of this paper is available at: http://www.insp.mx/salud/index.html.


Whistle-blowing process in healthcare: From suspicion to action.
Whistle-blowing is an ethical activity that tries to end wrongdoing. Wrongdoing in healthcare varies from inappropriate behaviour to illegal action. Whistle-blowing can have negative consequences for the whistle-blower, often in the form of bullying or retribution. Despite the wrongdoing and negative tone of whistle-blowing, there is limited literature exploring them in healthcare. The aim was to describe possible wrongdoing in Finnish healthcare and to examine whistle-blowing processes described on the basis of the existing literature in healthcare as perceived by healthcare professionals. The study was a cross-sectional descriptive survey. The data were collected using the electronic questionnaire Whistle-blowing in Health Care and analysed statistically. A total of 397 Finnish healthcare professionals participated, 278 of whom had either suspected or observed wrongdoing in healthcare, which established the data for this article. Ethical approval was obtained from the Ethics Committee of the University (20/2015). Permission to conduct the study was received according to the organisation's policies. Wrongdoing occurs in healthcare, as 96% of the participants had suspected and 94% had observed wrongdoing. Regarding the frequency, wrongdoing was suspected (57%) and observed (52%) more than once a month. Organisation-related wrongdoing was the most common type of wrongdoing (suspected 70%, observed 66%). In total, two whistle-blowing processes were confirmed in healthcare: (1) from suspicion to consequences occurred to 27%, and (2) from observation to consequences occurred to 37% of the participants. Wrongdoing occurs in healthcare quite frequently. Whistle-blowing processes were described based on the existing literature, but two separate processes were confirmed by the empirical data. More research is needed on wrongdoing and whistle-blowing on it in healthcare.


Biphasic versus monophasic oral contraceptives for contraception.
Side effects caused by oral contraceptives discourage compliance with, and continuation of, oral contraceptives. Three approaches have been used to decrease these adverse effects: reduction of steroid dose, development of new steroids, and new formulas and schedules of administration. The third strategy led to the biphasic oral contraceptive pill. To compare biphasic with monophasic oral contraceptives in terms of efficacy, cycle control, and discontinuation due to side effects. Our a priori hypotheses were: (a) biphasic oral contraceptives are less effective than monophasic oral contraceptives in preventing pregnancy; (b) biphasic oral contraceptives cause more side effects, give poorer cycle control, and have lower continuation rates. We searched the computerized databases MEDLINE, EMBASE, POPLINE, LILACS and CENTRAL. In addition, we searched the reference lists of all potentially relevant articles and book chapters. We also contacted the authors of relevant studies and pharmaceutical companies in Europe and the USA. We included randomized controlled trials comparing any biphasic with any monophasic oral contraceptive when used to prevent pregnancy. We examined the studies found during the various literature searches for possible inclusion and assessed their methodology using Cochrane guidelines. We contacted the authors of all included studies and possibly randomized studies for supplemental information about methodology and outcome. We entered the data into RevMan, and calculated Peto odds ratios for the incidence of intermenstrual bleeding, absence of withdrawal bleeding, and study discontinuation due to intermenstrual bleeding. Only one trial of limited quality compared a biphasic and monophasic preparation. Percival-Smith 1990 examined 533 user cycles of a biphasic pill (500 microg norethindrone/35 microg ethinyl estradiol for 10 days, followed by 1000 microg norethindrone/35 microg ethinyl estradiol for 11 days; Ortho 10/11) and 481 user cycles of a monophasic contraceptive pill (1500 microg norethindrone acetate/30 microg ethinyl estradiol daily; Loestrin). The study found no significant differences in intermenstrual bleeding, amenorrhea and study discontinuation due to intermenstrual bleeding between the biphasic and monophasic oral contraceptive pills. Conclusions are limited by the identification of only one trial, the methodological shortcomings of that trial, and the absence of data on accidental pregnancies. However, the trial found no important differences in bleeding patterns between the biphasic and monophasic preparations studied. Since no clear rationale exists for biphasic pills and since extensive evidence is available for monophasic pills, the latter are preferred.


Coarctation of the aorta with infracardiac total anomalous pulmonary venous drainage: a rare combination.
A 7-day-old female neonate was referred to the pediatric emergency department due to cyanosis and respiratory distress. Her arterial oxygen saturation was 65%. The Coarctation of the aorta, infracardiac total anomalous pulmonary venous drainage without obstruction and pulmonary artery hypertension were diagnosed by echocardiography. Emergency corrective surgery was done without confirming the diagnosis with cardiac magnetic resonance imaging (MRI) or cardiac catheterization due to her poor clinical status. The postoperative course was uneventful and the patient was extubated after the sixth day of surgery and discharged after 14 days.


First-in-man six-month results of a surface-modified coronary stent system in native coronary stenosis.
In preclinical studies, a bare metal cobalt-chromium stent with an active surface oxide layer modification (BMSmod) has been shown to inhibit neointimal hyperplasia effectively. We sought to assess both the clinical safety and feasibility of the BMSmod. In this prospective, non-randomised, first-in-man multicentre study, a total of 31 patients with de novo coronary lesions, reference lumen diameters of 2.5-3.5 mm and lesion length ≤16 mm, were enrolled. Quantitative coronary angiography and optical coherence tomography (OCT) were performed at baseline and six-month follow-up. Primary angiographic and OCT endpoints included in-stent late lumen loss (LLL) and mean neointimal thickness at six months. The device-oriented composite endpoint (DoCE), defined as cardiac death, myocardial infarction not clearly attributable to a non-intervention vessel, and clinically indicated target lesion revascularisation (CI-TLR), was analysed according to the intention-to-treat principle. In 31 patients (33 lesions), the procedural success rate was 93.5%. At six months, angiographic LLL was 0.91±0.45 mm and binary angiographic restenosis occurred in 23.3% of lesions. Out of 33 lesions, OCT was performed in 27 lesions at both time points. Mean neointimal thickness amounted to 348±116 µm. At six months, the DoCE was 19.4% due to the occurrence of CI-TLR in five patients (including one late definite stent thrombosis of a non-study stent). In contrast to previous preclinical pathophysiological work, the BMSmod did not prevent neointimal hyperplasia in a first-in-man clinical setting.


Model for polygonal hydraulic jumps.
We propose a phenomenological model for the polygonal hydraulic jumps discovered by Ellegaard and co-workers [Nature (London) 392, 767 (1998); Nonlinearity 12, 1 (1999); Physica B 228, 1 (1996)], based on the known flow structure for the type-II hydraulic jumps with a "roller" (separation eddy) near the free surface in the jump region. The model consists of mass conservation and radial force balance between hydrostatic pressure and viscous stresses on the roller surface. In addition, we consider the azimuthal force balance, primarily between pressure and viscosity, but also including nonhydrostatic pressure contributions from surface tension in light of recent observations by Bush and co-workers [J. Fluid Mech. 558, 33 (2006); Phys. Fluids 16, S4 (2004)]. The model can be analyzed by linearization around the circular state, resulting in a parameter relationship for nearly circular polygonal states. A truncated but fully nonlinear version of the model can be solved analytically. This simpler model gives rise to polygonal shapes that are very similar to those observed in experiments, even though surface tension is neglected, and the condition for the existence of a polygon with N corners depends only on a single dimensionless number φ. Finally, we include time-dependent terms in the model and study linear stability of the circular state. Instability occurs for sufficiently small Bond number and the most unstable wavelength is expected to be roughly proportional to the width of the roller as in the Rayleigh-Plateau instability.


A comparative study of the pharmacokinetics of traditional and automated dosing/blood sampling systems using gabapentin.
The present study was undertaken to investigate the pharmacokinetics (PKs) of gabapentin as determined by traditional manual blood sampling and by using an automated dosing/blood sampling technique in awake and freely moving rats using combined liquid chromatography tandem mass-spectrometry (LC-MS/MS). PK comparisons were conducted by allocating rats into two groups; an automated dosing/blood sampling (ADI/ABS) group (IV study, n = 6 and intragastric study, n = 6) and a manual group (IV study, n = 6 and oral study, n = 6). A series of blood samples from carotid artery were taken at specified times and analyzed using a validated LC-MS/MS method. Various PK parameters like area under curve (AUC(inf)), maximum concentration, time to reach maximum concentration, terminal half life, distribution volume at the steady state, and total clearance were calculated and the two study groups were compared with respect to these parameters. Significant differences in PK parameters were observed between the manual group and the ADI/ABS group and respective bioavailability were measured (46.82 ± 19.45% and 61.54 ± 21.23%, respectively) which is 1.31-fold difference (P = 0.0051, P<0.05). The described ADI/ABS method was found to be a useful drug development tool for accelerating the pace of preclinical in vivo studies and for obtaining reliable and accurate PK parameters even from single animals as it minimized interanimal and physiological variations.


Identification of bronchioalveolar stem cells in normal lung and lung cancer.
Injury models have suggested that the lung contains anatomically and functionally distinct epithelial stem cell populations. We have isolated such a regional pulmonary stem cell population, termed bronchioalveolar stem cells (BASCs). Identified at the bronchioalveolar duct junction, BASCs were resistant to bronchiolar and alveolar damage and proliferated during epithelial cell renewal in vivo. BASCs exhibited self-renewal and were multipotent in clonal assays, highlighting their stem cell properties. Furthermore, BASCs expanded in response to oncogenic K-ras in culture and in precursors of lung tumors in vivo. These data support the hypothesis that BASCs are a stem cell population that maintains the bronchiolar Clara cells and alveolar cells of the distal lung and that their transformed counterparts give rise to adenocarcinoma. Although bronchiolar cells and alveolar cells are proposed to be the precursor cells of adenocarcinoma, this work points to BASCs as the putative cells of origin for this subtype of lung cancer.


Telephone-delivered nutrition and exercise counselling after auto-SCT: a pilot, randomised controlled trial.
Adverse changes in nutrition-related outcomes including quality of life (QoL) occur after PBSC transplantation. This randomised controlled trial aims to evaluate the impact of nutrition and exercise counselling provided at hospital discharge on nutritional status, body composition and QoL post transplantation. Usual care (UC) (n=19) received no intervention after discharge; extended care (EC) (n=18) received fortnightly telephone counselling from a dietitian and exercise physiologist up to 100 days post transplantation. Nutritional status (patient-generated subjective global assessment, and diet history), QoL (EORTC QLQ-C30 version 3) and body composition (air displacement plethysmography) were assessed at pre-admission, discharge and 100 days post transplantation. Intervention groups were compared using two-sample t-tests of changes in the outcomes; results were adjusted using analysis of covariance. EC exhibited clinically important but not statistically significant increases in protein intake (14.7 g; confidence interval (CI) 95% -6.5, 35.9, P=0.165), cognitive functioning (7.2; CI 95% -7.9, 22.2, P=0.337) and social functioning (16.5; CI 95% -7.3, 40.3, P=0.165) compared with UC. Relative to pre-admission, EC experienced less weight loss than UC (-3.3 kg; CI 95% -6.7, 0.2, P=0.062). Physical activity was not significantly different between the groups. Ongoing nutrition and exercise counselling may prevent further weight loss and improve dietary intake and certain QoL components in autologous PBSC transplantation patients following hospitalisation.


Development of a highly sensitive and specific enzyme-linked immunosorbent assay based on recombinant matrix protein for detection of avian pneumovirus antibodies.
The matrix (M) protein of avian pneumovirus (APV) was evaluated for its antigenicity and reliability in an enzyme-linked immunosorbent assay (ELISA) for diagnosis of APV infection, a newly emergent disease of turkeys in United States. Sera from APV-infected turkeys consistently contained antibodies to a 30-kDa protein (M protein). An ELISA based on recombinant M protein generated in Escherichia coli was compared with the routine APV ELISA that utilizes inactivated virus as antigen. Of 34 experimentally infected turkeys, 33 (97.1%) were positive by M protein ELISA whereas only 18 (52.9%) were positive by routine APV ELISA 28 days after infection. None of the serum samples from 41 uninfected experimental turkeys were positive by M protein ELISA. Of 184 field sera from turkey flocks suspected of having APV infection, 133 (72.3%) were positive by M protein ELISA whereas only 99 (53.8%) were positive by routine APV ELISA. Twelve serum samples, which were negative by M protein ELISA but positive by routine APV ELISA, were not reactive with either recombinant M protein or denatured purified APV proteins by Western analysis. This indicates that the samples had given false-positive results by routine APV ELISA. The M protein ELISA was over six times more sensitive than virus isolation (11.5%) in detecting infections from samples obtained from birds showing clinical signs of APV infection. Taken together, these results show that ELISA based on recombinant M protein is a highly sensitive and specific test for detecting antibodies to APV.


Hand-Washing Practices among Adolescents Aged 12-15 Years from 80 Countries.
The objectives were to (1) assess the prevalence of hand-washing practices across 80 countries and (2) assess frequency of hand-washing practice by economic status (country income and severe food insecurity), in a global representative sample of adolescents. Cross-sectional data from the Global School-based Student Health Survey 2003-2017 were analyzed. Data on age, sex, hand-washing practices in the past 30 days, and severe food insecurity (i.e., proxy of socioeconomic status) were self-reported. Multivariable logistic regression and meta-analysis with random effects based on country-wise estimates were conducted to assess associations. Adolescents (n = 209,584) aged 12-15 years [mean (SD) age 13.8 (1.0) years; 50.9% boys] were included in the analysis. Overall, the prevalence of hand-washing practices were as follows: never/rarely washing hands before eating (6.4%), after using toilet (5.6%), or with soap (8.8%). The prevalence of never/rarely washing hands after using the toilet (10.8%) or with soap (14.3%) was particularly high in low-income countries. Severe food insecurity was associated with 1.34 (95%CI = 1.25-1.43), 1.61 (95%CI = 1.50-1.73), and 1.44 (95%CI = 1.35-1.53) times higher odds for never/rarely washing hands before eating, after using the toilet, and with soap, respectively. A high prevalence of inadequate hand washing practices was reported, particularly in low-income countries and those with severe food insecurity. In light of the present COVID-19 pandemic and the rapid expansion being observed in low- and middle-income locations, interventions that disseminate good hand-washing practices are urgently required. Such interventions may also have cross-over benefits in relation to other poor sanitation-related diseases.


Multiple intracellular pathways for regulation of chloride secretion in cultured pig tracheal submucosal gland cells.
Tracheal submucosal glands are of great relative importance in the secretion of chloride and water to the airway lumen. This study aimed to examine whether the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in cyclic adenosine monophosphate (cAMP) or Ca2+-activated Cl- secretion. Regulation of Cl- secretion in cell cultures derived from pig tracheal submucosal gland acini was investigated by X-ray microanalysis. With or without preincubation with CFTR antisense oligodeoxynucleotide (5 microM). A significant decrease in cellular Cl and K concentration was induced by 5 mM 8-bromo-adenosine 3': 5'-cyclic monophosphate (8-bromo-cAMP), 3 microM calcium ionophore ionomycin, 200 microM 5'-uridine triphosphate (UTP) and 200 microM 5'-adenosine triphosphate (ATP), respectively. The decrease in cellular Cl content was significantly inhibited by the Cl- channel blocker 5-nitro-2-(3-phenylpropyl-amino)-benzoic acid (NPPB; 50 microm). Preincubation of the cells with CFTR antisense oligodeoxynucleotide significantly inhibited the 8-bromo-cAMP-induced decrease in Cl, whereas CFTR sense oligodeoxynucleotide had no effect. The effects of ionomycin, ATP or UTP were not blocked by either CFTR antisense oligodeoxynucleotide or CFTR sense oligodeoxynueleotide. To measure the cytosolic free calcium concentration ([Ca2+]i) the cells grown on glass coverslips were loaded with fura-2 tetraoxymethylester (fura-2 AM; 5 microM). The [Ca2+]i was measured as the fluorescence ratio of emission (340/380 nm). Ionomycin (3 microM) caused a rapid increase in [Ca2+]i followed by a sustained plateau, but 8-bromo-cAMP had a more complex effect on [Ca2+]i. Exposure to ATP or UTP caused a rapid increase in [Ca2+]i followed by a decrease. In conclusion, cystic adenosine monophosphate and ionomycin induced Cl- secretion through different intracellular pathways. Adenosine triphosphate and uridine triphosphate also induced Cl- secretion probably with Ca as an intracellular messenger. The cystic fibrosis transmembrane conductance regulator is not involved in Cl- secretion activated by extracellular adenosine triphosphate and uridine triphosphate.


A comparison of 120 W laser photoselective vaporization versus transurethral resection of the prostate for bladder outlet obstruction by prostate cancer.
To compare the mid-term outcomes of photoselective vaporization of prostate (PVP) with GreenLight HPS 120 W laser and transurethral resection of the prostate (TURP) for obstructive lower urinary tract symptoms (LUTS) in men with prostate cancer (CaP). Seventy four patients with locally advanced (T3/T4) CaP with severe LUTS or acute urinary retention (AUR) were allocated to TURP (n = 36) or PVP (n = 38). International Prostate Symptom Scores (IPSS), maximum flow rates (Qmax) and post-void residual volumes (Vres), PSA levels, prostate volumes, complications, catheter removal and hospitalization periods were recorded. Patients were reassessed at 3, 6, and 12 months. The catheter removal time was significantly longer in the TURP group (3.8 ± 1.1 vs. 1.2 ± 0.7 days, p = 0.02), whereas failure of initial voiding trial was higher in PVP (2.7 vs. 13.1%, p = 0.01). No significant difference in IPSS, Qmax and Vres values was observed within the follow-up period between two groups. A significant difference in urethral stricture rate (8.3 vs. 0%), catheter removal time (3.8 ± 11 vs. 1.2 ± 0.7 days) and hospital stay (2.9 ± 0.6 vs. 1.1 ± 0.5 days) was observed in favor of PVP. Palliative PVP is very safe and effective by means of symptomatic relief in patients with locally advanced CaP.


Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).
To determine whether there were racial differences in short-term cardiometabolic responses to once-weekly exenatide (EQW) in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). EXSCEL enrolled 14,752 patients with type 2 diabetes (hemoglobin A1c (HbA1c) 6.5-10.0% [48-86 mmol/mol]) with or without cardiovascular disease who were randomized double-blind to EQW or placebo. Background glucose-lowering/other cardiovascular therapies were unaltered for 6 months post-randomization unless clinically essential, facilitating comparison of EQW-associated effects in 14,665 evaluable participants self-identifying as White (n = 11,113), Asian (n = 1444), Black (n = 870), or Other Race (n = 1,238. Placebo-adjusted 6 month absolute changes in cardiometabolic variables were assessed using generalized linear models. Mean 6-month placebo-adjusted HbA1c reductions were similar in the four groups (range 0.54-0.67% [5.9 to 7.3 mmol/mol], P = 0.11 for race×treatment interaction), with no significant difference in Asians (reference) versus other groups after covariate adjustment (all P ≥ 0.10). Six-month placebo-adjusted mean changes in systolic (-1.8 to 0.0 mmHg) and diastolic (0.2 to 1.2 mmHg) blood pressure, serum LDL (- 0.06 to 0.02 mmol/L) and HDL (0.00 to 0.01 mmol/L) cholesterol, and serum triglycerides (-0.1 to 0.0 mmol/L) were similar in the racial groups (P ≥ 0.19 for race×treatment interaction and all P ≥ 0.13 for comparisons of Asians with other races). Resting pulse rate increased more in Asians (4 beats/min) than in other groups (≤ 3 beats/min, P = 0.016 for race×treatment interaction and all P ≤ 0.050 for comparisons of Asians with other races). Short-term cardiometabolic responses to EQW were similar in the main racial groups in EXSCEL, apart from a greater pulse rate increase in Asians. https://clinicaltrials.gov NCT01144338.


Leaf Colour as a Signal of Chemical Defence to Insect Herbivores in Wild Cabbage (Brassica oleracea).
Leaf colour has been proposed to signal levels of host defence to insect herbivores, but we lack data on herbivory, leaf colour and levels of defence for wild host populations necessary to test this hypothesis. Such a test requires measurements of leaf spectra as they would be sensed by herbivore visual systems, as well as simultaneous measurements of chemical defences and herbivore responses to leaf colour in natural host-herbivore populations. In a large-scale field survey of wild cabbage (Brassica oleracea) populations, we show that variation in leaf colour and brightness, measured according to herbivore spectral sensitivities, predicts both levels of chemical defences (glucosinolates) and abundance of specialist lepidopteran (Pieris rapae) and hemipteran (Brevicoryne brassicae) herbivores. In subsequent experiments, P. rapae larvae achieved faster growth and greater pupal mass when feeding on plants with bluer leaves, which contained lower levels of aliphatic glucosinolates. Glucosinolate-mediated effects on larval performance may thus contribute to the association between P. rapae herbivory and leaf colour observed in the field. However, preference tests found no evidence that adult butterflies selected host plants based on leaf coloration. In the field, B. brassicae abundance varied with leaf brightness but greenhouse experiments were unable to identify any effects of brightness on aphid preference or performance. Our findings suggest that although leaf colour reflects both levels of host defences and herbivore abundance in the field, the ability of herbivores to respond to colour signals may be limited, even in species where performance is correlated with leaf colour.


Inositol 1,4,5-trisphosphate receptor down-regulation is activated directly by inositol 1,4,5-trisphosphate binding. Studies with binding-defective mutant receptors.
Activation of certain phosphoinositidase C-linked cell surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate (InsP3) receptors and, thus, lead to InsP3 receptor down-regulation. To gain insight into this process, we examined whether or not InsP3 receptor degradation is a direct consequence of InsP3 binding by analyzing the down-regulation of exogenous wild-type and binding-defective mutant InsP3 receptors expressed in SH-SY5Y human neuroblastoma cells. Stimulation of these cells with carbachol showed that wild-type exogenous receptors could be down-regulated but that the binding-defective mutant exogenous receptors were not. Thus, InsP3 binding appears to mediate down-regulation. To validate this conclusion, a comprehensive analysis of the effects of the exogenous receptors was undertaken. This showed that exogenous receptors (i) are localized appropriately within the cell, (ii) enhance InsP3-induced Ca2+ release in permeabilized cells, presumably by increasing the number of InsP3-sensitive Ca2+ channels, (iii) have minimal effects on Ca2+ mobilization and InsP3 formation in intact cells, (iv) form heteromers with endogenous receptors, and (v) do not alter the down-regulation of endogenous receptors. In total, these data show that the introduction of exogenous receptors into SH-SY5Y cells does not compromise intracellular signaling or the down-regulatory process. We can thus conclude that InsP3 binding directly activates InsP3 receptor degradation. Because InsP3 binding induces a conformational change in the InsP3 receptor, these data suggest that this change provides the signal for accelerated proteolysis.


[The effect of Ai Chi method in fibromyalgic patients].
The objective of this article is to show the effect of the Ai Chi method, as an alternative form of hydrotherapeutic approach in fibromyalgia syndrome patients. Ten patients were studied, four were part of the experiment group and five of the control group, with one desistance. The patients were evaluated through the Fibromyalgia Impact Questionnaire (QIF) and Scale of Intensity and Index of pain in Sensible Points. Two evaluations were performed, before and after the treatment. The patients were submitted to ten sessions of the Ai Chi method during 40 minutes. The scale of intensity of pain in sensible points presented an improvement in the intensity of pain after the intervention, while quality of life remained without alteration. Regarding the quality of life, it was observed that the groups had similar results, because of the fact that patients had not presented improvement at depressive state. It was also verified a difference in the index of the sensible points between the groups; the explanation for this difference might be because of the benefits of the immersion in warm water and the effect of the Ai Chi method. There was no significant difference between the groups, which can be attributed to its limitations. In this way, new studies referring to the application of the Ai Chi method in patients carrying fibromyalgia syndrome become relevant.


Adenine phosphoribosyltransferase deficiency: a simple diagnostic test.
1. A simple method for diagnosing adenine phosphoribosyltransferase (APRT) deficiency using urine is described. 2. T.l.c. of 1 microliter urine from a child with APRT deficiency was performed and adenine was easily detected by its brilliant blue phosphorescence at liquid nitrogen temperature. 3. Four physicochemical characteristics of adenine were recorded: RF value, and the colour, decay time and pH sensitivity of phosphorescence. 4. Adenine was not detected in the urine of 116 subjects used as controls. These included healthy individuals and patients with inherited metabolic disorders, diseases of purine metabolism and of the kidney and urinary tract. Some of them were taking a variety of drugs including purine derivatives. 5. The test correctly diagnosed three cases of APRT deficiency out of 10 urine samples tested blind.


DNA methylation changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study.
Aberrant DNA methylation is a major epigenetic mechanism of gene silencing in a wide range of human cancers. Previous studies on DNA methylation typically used paired tumor and normal-appearing surrounding tissues from cancer-bearing individuals. However, genomic DNA isolated from surrogate tissues such as blood cells represents an attractive material that can be exploited in the discovery of biomarkers of exposure and tumorigenesis. Here we examined the association between lung cancer and DNA methylation patterns in a panel of candidate genes. We also investigated whether blood levels of vitamin metabolites modify DNA methylation levels in blood cells. To this end, we quantitatively determined DNA methylation levels in blood cells of nested cases and controls from a prospective study with well defined dietary habits and lifestyles. Multiple CpG sites in five genes (CDKN2A/p16, RASSF1A, GSTP1, MTHFR, and MGMT) that are frequent targets of hypermethylation in a variety of human malignancies were included in the analysis. While no clear association between DNA methylation patterns and the case/control status was found, with the exception of RASSF1A hypermethylation, methylation level changed according to serum levels of 1-carbon metabolites and vitamins B. Overall, folate was associated with increased methylation levels of RASSF1A and MTHFR and methionine was associated with decreased methylation levels of RASSF1A. The associations with folate were more pronounced among never smokers while the associations with methionine were more evident among ever-smokers. These results are consistent with the notion that blood levels of 1-carbon metabolism markers and dietary/lifestyle factors may modify DNA methylation levels in blood cells and that blood cells can be exploited for the discovery of epigenetic biomarkers of exposures, providing proof-of-principle on the use of blood samples in the context of prospective studies.


Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65(495-503)-specific CD8+ T cells in older adults.
In immunocompetent individuals, cytomegalovirus (CMV) is thought to persist in a latent state in monocytes and myeloid progenitor cells, establishing a lifelong infection. In CMV-seropositive older adults, aging has been associated with both expansion of CMV pp65(495-503)-specific CD8(+) T cell clones and shrinkage of the T cell repertoire that characterize T cell immunosenescence. In fact it has been suggested that chronic CMV infection is a driving force in age-related T cell immunosenescence. In older adults, chronic CMV infection is conventionally diagnosed by positive IgG serology which does not distinguish between past and persistent infections. To better define the relationship between chronic CMV infection and expansion of CMV pp65(495-503)-specific CD8(+) T cells, we directly assessed CMV viral DNA in monocyte-enriched peripheral blood mononuclear cells in 16 HLA-A2-positive elderly volunteers (mean age = 83 years). While all participants had positive CMV IgG serology by enzyme-linked immunosorbent assays, only nine (56%) had detectable CMV DNA by nested polymerase chain reaction. These nine individuals had significantly higher percentages of CMV pp65(495-503) tetramer-positive CD8(+) T cells (median = 1.3%) than those without detectable CMV DNA (median = 0.1%; p < 0.001). Absolute CMV IgG antibody titers did not differ between these two groups (median = 54.6 vs 44.2 EU/ml, respectively, p = 0.4). CMV IgM titers were negative for all 16 participants, suggesting that recent primary CMV infection was unlikely. These results demonstrate a strong association between the presence of CMV DNA in peripheral monocytes and the expansion of CD8(+) T cells specific for the CMV immunodominant epitope pp65(495-503). Although the sample size in this study is relatively small, these findings provide initial evidence suggesting the heterogeneity of CMV IgG-seropositive older adult population and CMV viral DNA detection in peripheral monocytes as an informative tool to better understand the relationship between chronic CMV infection and T cell immunosenescence.


Frequent users of pornography. A population based epidemiological study of Swedish male adolescents.
Frequent use of pornography has not been sufficiently studied before. In a Swedish survey 2015 male students aged 18 years participated. A group of frequent users of pornography (N = 200, 10.5%) were studied with respect to background and psychosocial correlates. The frequent users had a more positive attitude to pornography, were more often "turned on" viewing pornography and viewed more often advanced forms of pornography. Frequent use was also associated with many problem behaviours. A multiple logistic regression analysis showed that frequent users of pornography were more likely to be living in a large city, consuming alcohol more often, having greater sexual desire and had more often sold sex than other boys of the same age. High frequent viewing of pornography may be seen as a problematic behaviour that needs more attention from both parents and teachers and also to be addressed in clinical interviews.


The Icare HOME (TA022) Study: Performance of an Intraocular Pressure Measuring Device for Self-Tonometry by Glaucoma Patients.
To evaluate the Icare HOME (TA022) device (Icare Oy, Vanda, Finland) for use by glaucoma patients for self-tonometry. Prospective performance evaluation of a medical device. One hundred eighty-nine participants with glaucoma or suspected glaucoma were recruited from the Wilmer Eye Institute, Baltimore, Maryland, between July 2014 and April 2015. Participants had standardized training and had to be able use the Icare HOME device independently. Subjects also had to be able to obtain the first intraocular pressure (IOP) measurement within 5 mmHg of Goldmann applanation tonometry (GAT). Those certified obtained 3 IOP measures using the HOME device, and these were compared with Icare TA01i and GAT IOP measurements. The agreement between Icare HOME and reference tonometers was used to assess precision. The intraclass correlation coefficient was used to assess within-patient reliability for the HOME device. Eighteen of 189 recruited patients were ineligible to take part in the study. Forty-four of 171 patients (25.7%) started but failed to complete the study: 7 stopped because of time concerns, 10 of 171 patients (6%) stopped because of difficulty using the device during certification, and 27 of 171 patients (16%) failed to be certified based on IOP. The HOME and GAT measurements agreed within 5 mmHg in 116 of 127 participants (91.3%); 2 participants (1.6%) had a difference of more than 7 mmHg. The mean difference between the Icare HOME and GAT measurements was -0.33 mmHg (standard deviation, 3.11 mmHg). The overall intraclass correlation coefficient for the HOME device was 0.92 (95% confidence interval, 0.89-0.95). Not all participants could learn how to use the Icare HOME device, but for those who could, most were able to obtain measurements similar to those obtained by GAT. The Icare HOME device is safe and reliable for self-tonometry, but nearly 1 in 6 individuals may fail to certify in use of the device based on large differences in IOP when comparing GAT with the Icare HOME measurements. The device has the potential to address an unmet need by providing more frequent IOP measurements in a patient's day to day life.


Diagnostic accuracy of OCT with a normative database to detect diffuse retinal nerve fiber layer atrophy: Diffuse Atrophy Imaging Study.
To investigate the diagnostic accuracy of Stratus optical coherence tomography (OCT) with its internal normative database to detect diffuse retinal nerve fiber layer (RNFL) atrophy in glaucoma subjects. One hundred two eyes of 102 glaucoma patients with diffuse RNFL atrophy and 102 healthy eyes of 102 age-matched subjects were enrolled in the Diffuse Atrophy Imaging Study. Two experienced observers graded RNFL photographs of diffuse RNFL atrophy eyes using a four-level grading system. The diagnostic performances for detecting diffuse RNFL atrophy were examined according to visual field results and RNFL photograph grading. Using a criterion of abnormal at the <5% level, the overall sensitivity of the Stratus OCT parameters ranged from 61.5% to 84.5%, and the overall specificity ranged from 90.2% to 99.0%. For mild, moderate, and severe diffuse RNFL atrophy, the superior quadrant had a sensitivity of 41.0%, 83.3%, and 100.0%, respectively, and the inferior quadrant had a sensitivity of 35.0%, 88.5%, and 100.0%, respectively. The highest likelihood ratios were obtained at the 11 and 12 o'clock sectors for superior RNFL and the 6 and 7 o'clock sectors for inferior RNFL. OCT with a normative database can detect diffuse RNFL atrophy with moderate sensitivity and high specificity. Because the sensitivity of Stratus OCT is closely related to the degree of diffuse RNFL atrophy and the visual field results, OCT with an internal normative database should be evaluated with prudence, especially in the early stage of glaucoma with diffuse RNFL atrophy.


Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction.
Glucocorticoids (GCs) have been used for more than 50 y as immunosuppressive drugs, yet their efficacy in macrophage-dominated disorders, such as chronic obstructive pulmonary disease, is debated. Little is known how long-term GC treatment affects macrophage responses in inflammatory conditions. In this study, we compared the transcriptome of human macrophages, matured in the presence or absence of fluticasone propionate (FP), and their ability to initiate or sustain classical activation, mimicked using acute LPS and chronic IFN-γ stimulation, respectively. We identified macrophage gene expression networks, modulated by FP long-term exposure, and specific patterns of IFN-γ- and LPS-induced genes that were resistant, inhibited, or exacerbated by FP. Results suggest that long-term treatment with GCs weakens adaptive immune signature components of IFN-γ and LPS gene profiles by downmodulating MHC class II and costimulatory molecules, but strengthens innate signature components by maintaining and increasing expression of chemokines involved in phagocyte attraction. In a mouse model of chronic obstructive pulmonary disease, GC treatment induced higher chemokine levels, and this correlated with enhanced recruitment of leukocytes. Thus, GCs do not generally suppress macrophage effector functions, but they cause a shift in the innate-adaptive balance of the immune response, with distinct changes in the chemokine-chemokine receptor network.


Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model.
Osteoarthritis is a degenerative disease that strongly correlates with age and promotes the breakdown of joint cartilage and subchondral bone. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stromal cells (MSCs) isolated from adult tissues. It seems that MSCs derived from synovial joint tissues exhibit superior chondrogenic ability, but their unclear distribution and low frequency actually limit their clinical application. To date, the influence of aging on synovial joint derived MSCs' biological characteristics and differentiation abilities remains unknown, and a full understanding of the mechanisms involved in cellular aging is lacking. The aim of this study was therefore to investigate the presence of age-related alterations in synovial fluid MSCs and their influence on the potential ability of MSCs to differentiate toward chondrogenic phenotypes. Synovial fluid MSCs, isolated from healthy equine donors from 3 to 40 years old, were cultured in vitro and stimulated towards chondrogenic differentiation for up to 21 days. An equine model was chosen due to the high degree of similarity of the anatomy of the knee joint to the human knee joint and as spontaneous disorders develop that are clinically relevant to similar human disorders. The results showed a reduction in cell proliferation correlated with age and the presence of age-related tetraploid cells. Ultrastructural analysis demonstrated the presence of morphological features correlated with aging such as endoplasmic reticulum stress, autophagy, and mitophagy. Alcian blue assay and real-time PCR data showed a reduction of efficiency in the chondrogenic differentiation of aged synovial fluid MSCs compared to young MSCs. All these data highlighted the influence of aging on MSCs' characteristics and ability to differentiate towards chondrogenic differentiation and emphasize the importance of considering age-related alterations of MSCs in clinical applications.


The effect of central bank communication on sovereign bond yields: The case of Hungary.
In this article we investigate how the public communication of the Hungarian Central Bank's Monetary Council (MC) affects Hungarian sovereign bond yields. This research ties into the advances made in the financial and political economy literature which rely on extensive textual data and quantitative text analysis tools. While prior research demonstrated that forward guidance, in the form of council meeting minutes or press releases can be used as predictors of rate decisions, we are interested in whether they are able to directly influence asset returns as well. In order to capture the effect of central bank communication, we measure the latent hawkish or dovish sentiment of MC press releases from 2005 to 2019 by applying a sentiment dictionary, a staple in the text mining toolkit. Our results show that central bank forward guidance has an intra-year effect on bond yields. However, the hawkish or dovish sentiment of press releases has no impact on maturities of one year or longer where the policy rate proves to be the most important explanatory variable. Our research also contributes to the literature by applying a specialized dictionary to monetary policy as well as broadening the discussion by analyzing a case from the non-eurozone Central-Eastern region of the European Union.


Histological assessment of gastric pseudopyloric metaplasia: Intra- and inter-observer consistency.
The histological spectrum of oxyntic mucosal atrophy (a major determinant of gastric cancer risk) includes pseudopyloric metaplasia (PPM), which histological assessment has been regarded as unreliable. PPM consistently expresses Trefoil-Factor 2 (TFF2), which is histochemically detecteble (TFF2-IHC). Intra- and inter-observer consistency in assessing PPM was examined using both hematoxylin & eosin (H&E) and TFF2-IHC. Seventy-four oxyntic biopsy samples obtained from autoimmune gastritis were considered. Two serial histological sections obtained from the paraffin-embedded tissue-samples were stained with H&E and TFF2-IHC. Three pathologists (Alpha, Beta, Gamma) independently scored PPM by both staining and the Intra- and inter-observer consistency (H&E versus TFF2-IHC) was calculated using k-statistics and/or Spearman's coefficient. Based on H&E-stain versus TFF2-IHC, intra-observer consistency in PPM assessement was ranked as consistently "good" (k-values: Alpha=0.79; Beta=0.78; Gamma=0.75). Based on H&E, the overall PPM inter-observer consistency among the 3 observers was ranked as "good" (k=0.77) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=0.88; Alpha versus Gamma k=0.87; Beta versus Gamma k=0.80). Based on TFF2-IHC, the overall PPM inter-observer agreement was ranked as "excellent" (k=0.91) (the inter-observer consistency for pairs of observers was as follows: Alpha versus Beta k=1; Alpha versus Gamma k=0.91; Beta versus Gamma k=0.91). Relying on either H&E staining or TFF2-IHC, pathologists assess PPM consistently.


Palmitoylation cycles and regulation of protein function (Review).
The efficacy and success of many cellular processes is dependent on a tight orchestration of proteins trafficking to and from their site(s) of action in a time-controlled fashion. Recently, a dynamic cycle of palmitoylation/de-palmitoylation has been shown to regulate shuttling of several proteins, including the small GTPases H-Ras and N-Ras, and the GABA-synthesizing enzyme GAD65, between the Golgi compartment and either the plasma membrane or synaptic vesicle membranes. These proteins are peripheral membrane proteins that in the depalmitoylated state cycle rapidly on and off the cytosolic face of ER/Golgi membranes. Palmitoylation of one or more cysteines, by a Golgi localized palmitoyl transferase (PAT) results in trapping in Golgi membranes, and sorting to a vesicular pathway in route to the plasma membrane or synaptic vesicles. A depalmitoylation step by an acyl protein thioesterase (APT) releases the protein from membranes in the periphery of the cell resulting in retrograde trafficking back to Golgi membranes by a non-vesicular pathway. The proteins can then enter a new cycle of palmitoylation and depalmitoylation. This inter-compartmental trafficking is orders of magnitude faster than vesicular trafficking. Recent advances in identifying a large family of PATs, their protein substrates, and single PAT mutants with severe phenotypes, reveal their critical importance in development, synaptic transmission, and regulation of signaling cascades. The emerging knowledge of enzymes involved in adding and removing palmitate is that they provide an intricate regulatory network involved in timing of protein function and transport that responds to intracellular and extracellular signals.


Radiology reporting of obesity: a survey of patient and clinician attitudes.
To determine whether obesity information obtained via imaging techniques is desirable for clinicians and patients, and to investigate whether it impacts clinical decision-making. Parallel surveys were designed to assess patient and clinician attitudes to the medical utility and social stigma of reporting obesity on radiology reports performed for other reasons. Where obesity was noted at medical imaging performed for any reason, clinicians and patients strongly agreed that it should be included in the radiology report (5.9 and 5.8, respectively, on a seven-point preference score ranging from strongly disagree [1] to strongly agree [7]). Clinicians and patients indicated a preference for a quantitative report. Clinicians somewhat disagreed and patients disagreed that a radiology report describing obesity would be considered insulting (3 and 2.1, respectively). Clinicians and patients agreed that they would be more likely to discuss overweight/obesity if it was described in a radiology report (5.3 and 6.1 respectively). Clinicians and patients agreed that radiology reports describing obesity would influence future management/behaviour (4.5 and 6.2, respectively). Clinicians strongly disagreed that they would avoid sending patients for scans if obesity was reported (1.3). Patients also disagreed that including such information on a report would result in imaging avoidance (1.9). Both clinicians and patients indicate a clear preference for obesity-related information on radiology reports for examinations performed for any reason. Surveyed attitudes suggest including such information is not considered insulting, and is unlikely to result in avoidance of imaging.


AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews.
Our purpose was to measure the agreement, reliability, construct validity, and feasibility of a measurement tool to assess systematic reviews (AMSTAR). We randomly selected 30 systematic reviews from a database. Each was assessed by two reviewers using: (1) the enhanced quality assessment questionnaire (Overview of Quality Assessment Questionnaire [OQAQ]); (2) Sacks' instrument; and (3) our newly developed measurement tool (AMSTAR). We report on reliability (interobserver kappas of the 11 AMSTAR items), intraclass correlation coefficients (ICCs) of the sum scores, construct validity (ICCs of the sum scores of AMSTAR compared with those of other instruments), and completion times. The interrater agreement of the individual items of AMSTAR was substantial with a mean kappa of 0.70 (95% confidence interval [CI]: 0.57, 0.83) (range: 0.38-1.0). Kappas recorded for the other instruments were 0.63 (95% CI: 0.38, 0.78) for enhanced OQAQ and 0.40 (95% CI: 0.29, 0.50) for the Sacks' instrument. The ICC of the total score for AMSTAR was 0.84 (95% CI: 0.65, 0.92) compared with 0.91 (95% CI: 0.82, 0.96) for OQAQ and 0.86 (95% CI: 0.71, 0.94) for the Sacks' instrument. AMSTAR proved easy to apply, each review taking about 15 minutes to complete. AMSTAR has good agreement, reliability, construct validity, and feasibility. These findings need confirmation by a broader range of assessors and a more diverse range of reviews.


Electric field makes Leidenfrost droplets take a leap.
Leidenfrost droplets, i.e. droplets whose mobility is ensured by a thin vapor film between the droplet and a hot plate, are exposed to an external electric field. We find that in a strong vertical electric field the droplet can start to bounce progressively higher, defying gravitational attraction. From the droplet's trajectory we infer the temporal evolution of the amount of charge on the droplet. This reveals that the charge starts high and then decreases in steps as the droplet slowly evaporates. After each discharge event the charge is in a fixed proportion to the droplet's surface area. We show that this behavior can be accurately modeled by treating the droplet as a conducting sphere that occasionally makes electrical contact with the hot plate, at intervals dictated by an electro-capillary instability in the vapor film. An analysis of the kinetic and potential energies of the bouncing droplet reveals that, while the overall motion is damped, the droplet occasionally experiences a sudden boost, keeping its energy close to the value for which the free fall trajectory and droplet oscillation are in sync. This helps the droplet to escape from the hot surface when finally the electrical surface forces overtake gravity.


Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion.
We describe a new focal ischemia model consisting of unilateral middle cerebral artery occlusion with a silicone rubber cylinder attached to a nylon surgical thread inserted through the internal carotid artery in rats. Recirculation was accomplished by pulling the thread out of the artery. We evaluated the reliability of this model and studied the influence of reperfusion of the brain by measuring regional cerebral blood flow in 30 rats and by using conventional neuropathologic methods after different periods of occlusion in 48 rats. The anterior neocortex and the lateral part of the caudate putamen, which were supplied by the occluded middle cerebral artery, were the regions most frequently damaged. After 1 hour of occlusion in five rats, in the cortex supplied by the occluded artery mean +/- SD blood flow was 0.19 +/- 0.08 ml/g/min (approximately 15% of that in the corresponding region of five sham-operated control rats), and mild scattered ischemic cell change was observed. Three (n = 5) or six (n = 5) hours of occlusion reduced blood flow more severely and caused severe ischemic cell changes in the cortex supplied by the occluded artery in proportion to the duration of ischemia. Characteristically, in five rats subjected to 3 hours of occlusion followed by 3 hours of recirculation, blood flow was restored and spongy edematous change was observed in the cortex supplied by the recirculated artery. This change resulted in hypoperfusion of the neighboring cortical region surrounding the recirculated area. Our model should be useful in various investigations of the influence of reperfusion on focal ischemic brain injury.


Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone.
Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.


Venous-arterial extracorporeal membrane oxygenation for refractory cardiac arrest: a clinical challenge.
Guidelines stated that extracorporeal membrane oxygenation (ECMO) may improve outcomes after refractory cardiac arrest (CA) in cases of cardiogenic shock and witnessed arrest, where there is an underlying circulatory disease amenable to immediate corrective intervention. Due to the lack of randomized trials, available data are supported by small series and observational studies, being therefore characterized by heterogeneity and controversial results. In clinical practice, using ECMO involves quite a challenging medical decision in a setting where the patient is extremely vulnerable and completely dependent on the medical team's judgment. The present review focuses on examining existing evidence concerning inclusion and exclusion criteria, and outcomes (in-hospital and long-term mortality rates and neurological recovery) in studies performed in patients with refractory CA treated with ECMO. Discrepancies can be related to heterogeneity in study population, to differences in local health system organization in respect of the management of patients with CA, as well as to the fact that most investigations are retrospective. In the real world, patient selection occurs individually within each center based on their previous experience and expertise with a specific patient population and disease spectrum. Available evidence strongly suggests that in CA patients, ECMO is a highly costly intervention and optimal utilization requires a dedicated local health-care organization and expertise in the field (both for the technical implementation of the device and for the intensive care management of these patients). A careful selection of patients guarantees optimal utilization of resources and a better outcome.


Status of immune mediators in fibromyalgia.
Fibromyalgia (FM) is a form of nonarticular rheumatism characterized by long-term (> 3 months) and widespread musculoskeletal pain. However, the biophysiology of FM has remained elusive, and the treatment remains mainly empirical. There are numerous hypotheses about the pathophysiology of chronic widespread pain and FM; one includes a possible role of cytokines. Cytokines play a role in diverse clinical processes and phenomena such as fatigue, fever, sleep, pain, stress, and aching. Cytokines related to acute or repetitive tissue injuries may be responsible for long-term activation of spinal cord glia and dorsal horn neurons, thus resulting in central sensitization. Pain, stiffness, and depression in FM could be associated with some signs of inflammatory response system activation. Illumination of the pathophysiologic secrets of FM will result in more effective treatment regimens. We review the role of immune mediators in the pathophysiology of FM.


Bacillus pumilus SAFR-032 Genome Revisited: Sequence Update and Re-Annotation.
Bacillus pumilus strain SAFR-032 is a non-pathogenic spore-forming bacterium exhibiting an anomalously high persistence in bactericidal environments. In its dormant state, it is capable of withstanding doses of ultraviolet (UV) radiation or hydrogen peroxide, which are lethal for the vast majority of microorganisms. This unusual resistance profile has made SAFR-032 a reference strain for studies of bacterial spore resistance. The complete genome sequence of B. pumilus SAFR-032 was published in 2007 early in the genomics era. Since then, the SAFR-032 strain has frequently been used as a source of genetic/genomic information that was regarded as representative of the entire B. pumilus species group. Recently, our ongoing studies of conservation of gene distribution patterns in the complete genomes of various B. pumilus strains revealed indications of misassembly in the B. pumilus SAFR-032 genome. Synteny-driven local genome resequencing confirmed that the original SAFR-032 sequence contained assembly errors associated with long sequence repeats. The genome sequence was corrected according to the new findings. In addition, a significantly improved annotation is now available. Gene orders were compared and portions of the genome arrangement were found to be similar in a wide spectrum of Bacillus strains.


Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization.
Human factor VIII--von Willebrand factor (vWF) is a large, multimeric glycoprotein that plays a central role in the blood coagulation system, serving both as a carrier for factor VIIIC (antihemophilic factor) and as a major mediator of platelet-vessel wall interaction. Diminished or abnormal vWF activity results in von Willebrand's disease (vWD), a common and complex hereditary bleeding disorder. Overlapping vWF cDNA clones that span 8.2 kilobases of the vWF messenger RNA have been obtained. vWF accounts for approximately 0.3 percent of endothelial cell messenger RNA and was undetectable in several other tissues examined. A large single copy gene for vWF is located on the short arm of chromosome 12 (12p12----12pter). No gross gene rearrangement or deletion was detected in the DNA of two patients with severe vWD.


The double-stranded RNA binding domain of human Dicer functions as a nuclear localization signal.
Dicer is a key player in microRNA (miRNA) and RNA interference (RNAi) pathways, processing miRNA precursors and double-stranded RNA into ∼21-nt-long products ultimately triggering sequence-dependent gene silencing. Although processing of substrates in vertebrate cells occurs in the cytoplasm, there is growing evidence suggesting Dicer is also present and functional in the nucleus. To address this possibility, we searched for a nuclear localization signal (NLS) in human Dicer and identified its C-terminal double-stranded RNA binding domain (dsRBD) as harboring NLS activity. We show that the dsRBD-NLS can mediate nuclear import of a reporter protein via interaction with importins β, 7, and 8. In the context of full-length Dicer, the dsRBD-NLS is masked. However, duplication of the dsRBD localizes the full-length protein to the nucleus. Furthermore, deletion of the N-terminal helicase domain results in partial accumulation of Dicer in the nucleus upon leptomycin B treatment, indicating that CRM1 contributes to nuclear export of Dicer. Finally, we demonstrate that human Dicer has the ability to shuttle between the nucleus and the cytoplasm. We conclude that Dicer is a shuttling protein whose steady-state localization is cytoplasmic.


Plastic leachates impair growth and oxygen production in Prochlorococcus, the ocean's most abundant photosynthetic bacteria.
Plastic pollution is a global threat to marine ecosystems. Plastic litter can leach a variety of substances into marine environments; however, virtually nothing is known regarding how this affects photosynthetic bacteria at the base of the marine food web. To address this, we investigated the effect of plastic leachate exposure on marine Prochlorococcus, widely considered the most abundant photosynthetic organism on Earth and vital contributors to global primary production and carbon cycling. Two strains of Prochlorococcus representing distinct ecotypes were exposed to leachate from common plastic items: high-density polyethylene bags and polyvinyl chloride matting. We show leachate exposure strongly impairs Prochlorococcus in vitro growth and photosynthetic capacity and results in genome-wide transcriptional changes. The strains showed distinct differences in the extent and timing of their response to each leachate. Consequently, plastic leachate exposure could influence marine Prochlorococcus community composition and potentially the broader composition and productivity of ocean phytoplankton communities.


Outcomes in anticoagulated patients with atrial fibrillation and with mitral or aortic valve disease.
To assess stroke/systemic embolism, major bleeding and other outcomes, and treatment effect of apixaban versus warfarin, in patients with atrial fibrillation (AF) and different types of valvular heart disease (VHD), using data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. There were 14 793 patients with known VHD status, categorised as having moderate or severe mitral regurgitation (MR) (n=3382), aortic regurgitation (AR) (n=842) or aortic stenosis (AS) (n=324); patients with moderate or severe mitral stenosis were excluded from the trial. Baseline characteristics, efficacy and safety outcomes were compared between each type and no significant VHD. Treatment effect was assessed using an adjusted model. Patients with MR or AR had similar rates of stroke/systemic embolism and bleeding compared with patients without MR or AR, respectively. Patients with AS had significantly higher event rates (presented as rate per 100 patient-years of follow-up) of stroke/systemic embolism (3.47 vs 1.36; adjusted HR (adjHR) 2.21, 95% CI 1.35 to 3.63), death (8.30 vs 3.53; adjHR 1.92, 95% CI 1.41 to 2.61), major bleeding (5.31 vs 2.53; adjHR 1.80, 95% CI 1.19 to 2.75) and intracranial bleeding (1.29 vs 0.51; adjHR 2.54, 95% CI 1.08 to 5.96) than patients without AS. The superiority of apixaban over warfarin on stroke/systemic embolism was similar in patients with versus without MR (HR 0.69, 95% CI 0.46 to 1.04 vs HR 0.79, 95% CI 0.63 to 1.00; interaction P value 0.52), with versus without AR (HR 0.57, 95% CI 0.27 to 1.20 vs HR 0.78, 95% CI 0.63 to 0.96; interaction P value 0.52), and with versus without AS (HR 0.44, 95% CI 0.17 to 1.13 vs HR 0.79, 95% CI 0.64 to 0.97; interaction P value 0.19). For each of the primary and secondary efficacy and safety outcomes, there was no evidence of a different effect of apixaban over warfarin in patients with any VHD subcategory. In anticoagulated patients with AF, AS is associated with a higher risk of stroke/systemic embolism, bleeding and death. The efficacy and safety benefits of apixaban compared with warfarin were consistent, regardless of presence of MR, AR or AS. ARISTOTLE clinical trial number NCT00412984.


The effect of LRRK2 loss-of-function variants in humans.
Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes1,2. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease3,4, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns5-8, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)9, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work10, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.


Effect of Calcium Salts Concentration on the Viscoelastic Properties of Sintered Tablets from Flours and Tortillas Evaluated by Stress-Relaxation Tests.
This research aimed to evaluate the effect of different calcium compounds and their concentration on the viscoelastic parameters of flours and tortillas obtained with traditional and ecological nixtamalization. Specimens (tablets) of nixtamalized flours and tortillas (14% moisture) prepared with three different calcium sources and four concentrations were sintered using a die and a hydraulic press and were evaluated by stress-relaxation tests with a texturometer. Data collected from the stress-relaxation curve were fitted into a three-element generalized Maxwell model (r2 = 0.9999), allowing the detection of significant differences in the estimated viscoelastic parameters. When flours are processed into tortillas, the most notable change was the increase of +88.44% and +73.44%, respectively, in the summation of the elastic modulus, and the compressional viscosity in samples produced with CaCO3. On the contrary, tablets from samples with Ca(OH)2 presented a sharp diminishing (loss) in both of the evaluated viscoelastic parameters, accounting a decrease of -39.82% and -46.28% for the elastic modulus and compressional viscosity summations, respectively. Highly significant correlations were found among viscoelastic parameters when a slight proportional increase was observed in the specific elastic moduli, meaning that the energy was stored by each elastic element in the tablets, while the compressional viscosity coefficients varied as a function of time. Finally, it was found that the residual spring due to the pure elastic component (E0 ) stored energy during the entire test. PRACTICAL APPLICATION: There is no published information about a simple methodology for the evaluation of the viscoelastic properties of dry nixtamalized flours (powder) with a texturometer. The method proposed was sensitive and accurate, since it was capable of detecting differences among samples processed under distinct processing factors conditions. The study of viscoelastic properties of grain foods contributes to the construction of molecular theories occurring in their chemical compounds, which is strongly related to food texture. Those theories are handy to improve nutritional and textural properties of grain foods and are essential to powder handling, processing, and transportation, which allows the processing factors optimization.


METABOLIC SYNDROME AND ITS COMPONENTS IN SPANISH POSTMENOPAUSAL WOMEN.
this study aimed to estimate prevalence of metabolic syndrome and all its components to know the cardiovascular risk and metabolic control of the main risk factors in postmenopausal women aged over 45 years in the province of Cuenca (Castilla-La Mancha, Spain). in this cross-sectional study, we randomly selected 716 postmenopausal women from 3,108 women aged over 45. Metabolic syndrome was identified according to the National Cholesterol Education Program Adult Treatment Panel III definition. Cardiovascular risk was calculated by the Systematic Coronary Risk Evaluation ( < 65 years). The American Diabetes Association´s standards of medical care in diabetes were used to estimate metabolic control. The statistical analysis was done with SPPS.19 RESULTS: prevalence of metabolic syndrome was 61.7% (95%CI: 56.9-66.4). Prevalence of each component was: high blood pressure: 95.8% (95%CI: 95.7-95.8), abdominal obesity: 91% (95%CI: 90.9-91.0), low high-density lipoproteins cholesterol (HDLc) levels: 70% (95%CI: 69.8-69.9), high triglyceride levels: 56.9% (95%CI: 56.4- 56.9), high glucose levels: 54.3% (95%CI: 54.2-54.3). Cardiovascular risk was moderate until 65 years, but was high after this age. Metabolic control in postmenopausal women was very good for glucose, bad for systolic blood pressure and worse for lipid levels. Bad blood pressure control was associated with being over 65 years, being hypertensive and taking treatment for diabetes, but it reduced when being physically limited to do moderate exercise and anxiety increased. prevalence of metabolic syndrome in postmenopausal women in the province of Cuenca is the highest in Spain. High blood pressure and abdominal obesity are the commonest components. Cardiovascular risk was moderate-high in postmenopausal women, but systolic blood pressure and lipid profile were unsatisfactorily controlled. Early intervention is necessary to achieve a better risk profile.


Subcutaneous fat necrosis with hypercalcemia.
We report the case of an infant with diffuse subcutaneous fat necrosis following birth asphyxia who had hypercalcemia and the rare complication of venous calcification. The clinical and radiologic findings resolved over 5 months. The disease is characterized by the presence of painless subcutaneous nodules, mainly over bony prominences, possibly associated with hypercalcemia and calcification. Early identification of hypercalcemia will avert its serious sequelae.


Flood basalts and hot-spot tracks: plume heads and tails.
Continental flood basalt eruptions have resulted in sudden and massive accumulations of basaltic lavas in excess of any contemporary volcanic processes. The largest flood basalt events mark the earliest volcanic activity of many major hot spots, which are thought to result from deep mantle plumes. The relative volumes of melt and eruption rates of flood basalts and hot spots as well as their temporal and spatial relations can be explained by a model of mantle plume initiation: Flood basalts represent plume "heads" and hot spots represent continuing magmatism associated with the remaining plume conduit or "tail." Continental rifting is not required, although it commonly follows flood basalt volcanism, and flood basalt provinces may occur as a natural consequence of the initiation of hot-spot activity in ocean basins as well as on continents.


Raman spectrum identification based on the correlation score using the weighted segmental hit quality index.
In this paper, we consider a novel method for identification of Raman spectra recorded on different instruments with different wavelengths. Since the conventional hit quality index (HQI) is vulnerable to intensity variation, it needs intensity calibration or standardization for each spectrometer, which causes additional time consuming work. To simplify this process and enhance the identification performance, we propose a new scoring method which is defined as the weighted sum of the HQIs from segmented spectra by windowing. To show the effectiveness of the proposed method, the experiments were carried out with 10 kinds of chemicals with their spectra recorded on 3 different instruments with different laser wavelengths. According to the identification results with 14 033 chemicals, the proposed method identified all test chemicals without error, which indicates that the proposed method could be used as a promising alternative to the existing methods.


Radioprotective effects of Silymarin on the sperm parameters of NMRI mice irradiated with γ-rays.
Free radicals and reactive oxygen species (ROS) are generated using various endogenous systems or from external sources such as exposure to different physiochemicals. Ionizing radiation damage to the cell can be caused by the direct or indirect effects of radiotherapy processes. Silymarin (SM), a flavanolignan compound, has been identified as a natural potent antioxidant with cytoprotection activities due to scavenging free radicals. The aim of the present study was to evaluate the radioprotective effect of SM on sperm parameters of mice induced by γ-rays. A total number of 40 adult, male NMRI mice were randomly divided into four equal groups. The control group was neither treated with SM nor irradiated by γ-rays. The second group was only irradiated with 2Gy of γ-rays. The third group was firstly treated with 50mg/kg of SM for 7 consecutive days, and one day later, last injections were irradiated by 2Gy of γ-rays. The fourth groups received only 50mg/kg of SM for 7 consecutive days. All the animals were treated intraperitoneally. Histopathological and morphometrical examinations were performed. The data were analyzed using ANOVA and Tukey post hoc test. A value of p<0.05 was considered significant. The results showed that in the radiation-only group when compared with those treated with SM and irradiated, a significant different was observed in testicular parameters and DNA damage (p<0.05). In conclusion, SM can be considered as a promising herbal radioprotective agent in complementary medicine which may play an important role to protect normal spermatocytes against possible effects of γ-radiation-induced cellular damage.


Effect of infliximab on acute hepatic ischemia/reperfusion injury in rats.
This study aimed to investigate the hepatoprotective and antioxidant effects of infliximab (IFX) against liver ischemia/reperfusion (I/R) injury in rats. A total of 30 male Wistar albino rats were divided into three groups: sham, I/R, and I/R+IFX. IFX was given at a dose of 3 mg/kg for three days before I/R. Rat livers were subjected to 60 min of ischemia followed by 90 h of reperfusion. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), TNF-α, malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) levels were measured in the serum. The liver was removed to evaluate the histopathologic changes. The I/R group had a significant increase in AST, ALT, MDA, and TNF-α levels, and a decrease in GSH-Px activity compared with the sham group. The use of IFX significantly reduced the ALT, AST, MDA and TNF-α levels and significantly increased GSH-Px activity. IFX attenuated the histopathologic changes. IFX has a protective effect on liver I/R injury. This liver protective effect may be related to antioxidant and anti-TNF-α effects. We propose that, for the relief of liver injury subsequent to transplantation, liver resection, trauma, and shock, tentative treatments can be incorporated with IFX, which is already approved for clinical use.


Thermal Resistance of Foodborne Pathogens and Enterococcus faecium NRRL B-2354 on Inoculated Pistachios.
Process control validations require knowledge of the resistance of the pathogen(s) of concern to the target treatment and, in some cases, the relative resistance of surrogate organisms. Selected strains of Escherichia coli O157:H7 (five strains), Listeria monocytogenes (five strains), and Salmonella enterica (five strains) as well as Salmonella Enteritidis phage type (PT) 30 and nonpathogenic Enterococcus faecium NRRL B-2354 were inoculated separately (as individual strains) onto inshell pistachios. The thermal tolerance of each strain was compared via treatment of inoculated pistachios to hot oil (121°C) or hot water (80°C) for 1 min. Survivor curves in hot oil or hot water (0.5 to 6 min, n = 6 to 15) were determined for one or two of the most resistant strains of each pathogen, as well as E. faecium NRRL B-2354 and Salmonella Enteritidis PT 30, and the Weibull model was fit to the data. A pilot-scale air-impingement oven was used to compare the thermal tolerance of E. faecium NRRL B-2354 and Salmonella Enteritidis PT 30 on pistachios with or without a brining pretreatment and at either dry (no steam) or 30% humidity (v/v) oven conditions. No significant difference in the time to a 4-log reduction in hot oil or hot water was predicted for any of the strains evaluated, on the basis of the 95% confidence interval. In the pilot-scale oven, E. faecium NRRL B-2354 was more thermally resistant than Salmonella in a broad set of differing treatments, treatment times, and temperatures. Salmonella is a suitable target pathogen of concern in pistachios for thermal processes because no other pathogen tested was more thermally resistant under the conditions evaluated. E. faecium NRRL B-2354 was at least as thermally resistant as Salmonella under all conditions evaluated, making it a good potential surrogate for Salmonella on pistachios.


Transcutaneous electrical acupoint stimulation in children with autism and its impact on plasma levels of arginine-vasopressin and oxytocin: a prospective single-blinded controlled study.
Acupuncture increases brain levels of arginine-vasopressin (AVP) and oxytocin (OXT), which are known to be involved in the modulation of mammalian social behavior. Transcutaneous electrical acupoint stimulation (TEAS) is often used clinically to produce a similar stimulation to that of acupuncture on the acupoints. In the present study, TEAS was applied to children with autism to assess its therapeutic efficacy. Seventy-six autistic children receiving rehabilitation training were divided into 2 groups: a treatment group receiving TEAS 30min per day, 5 days per week for 12 weeks (n=37) and a control group without TEAS treatment (n=39). A series of rating scales was used in outcome assessment. Plasma levels of AVP and OXT were determined by enzyme immunoassay (EIA) before and after treatment. The TEAS group showed a significant improvement over the control in their emotional response, fear or anxiety, level/consistency of intellective relations and general impressions on the Childhood Autism Rating Scale (CARS) as well as improvements in the sensory and related factors in the Autism Behavior Checklist (ABC). In addition, the varieties of accepted food increased after TEAS treatment. It appears that TEAS was effective in autistic children who showed passive and aloof behavior, but not in those who were active but odd. The plasma level of AVP was significantly higher in the TEAS group than in the control group after the intervention. In addition, the change in the plasma AVP level paralleled the improvement of some of the behavior factors in CARS, including adaptation to environmental change, listening response, perceptive response and fear or anxiety. It is concluded that TEAS is effective for the treatment of autistic children with a passive and aloof social interaction style. Changes in plasma levels of AVP and possibly OXT may be involved in mediating the therapeutic effect of TEAS.