bluuebunny/crossref_metadata_2025 huggingface dataset:
Pneumococcal conjugate vaccines PREVenar13 and SynflorIX in sequence or alone in high-risk Indigenous infants (PREV-IX_COMBO): protocol of a randomised controlled trial
Authors: Leach Amanda Jane , Mulholland Edward Kim , Santosham Mathu , Torzillo Paul John , Brown Ngiare Joy , McIntyre Peter , Smith-Vaughan Heidi , Skull Sue , Balloch Anne , Andrews Ross , Carapetis Jonathan , McDonnell Joseph , Krause Vicki , Morris Peter Stanley
Published: January 2015

Introduction

Otitis media (OM) starts within weeks of birth in almost all Indigenous infants living in remote areas of the Northern Territory (NT). OM and associated hearing loss persist from infancy throughout childhood and often into adulthood. Educational and social opportunities are greatly compromised.Pneumococcusand non-typeableHaemophilus influenzae(NTHi) are major OM pathogens that densely colonise the nasopharynx and infect the middle ear from very early in life. Our hypothesis is that compared to current single vaccine schedules, a combination of vaccines starting at 1 month of age, may provide earlier, broadened protection.

Methods and analyses

This randomised outcome assessor, blinded controlled trial will recruit 425 infants between 28 and 38 days of age and randomly allocate them (1:1:1) to one of three pneumococcal conjugate vaccine (PCV) schedules: Synflorix at 2, 4, 6 months of age, Prevenar13 at 2, 4 and 6 months of age, or an investigational schedule of Synflorix at 1, 2 and 4 months plus Prevenar13 at 6 months of age. The blinded primary outcomes at 7 months of age are immunogenicity of specific vaccine antigens (geometric mean concentration (GMC) and proportion of participants with above threshold GMC of 0.35 µg/L). Secondary outcomes at all timepoints are additional immunogenicity measures and proportion of participants with nasopharyngeal carriage of vaccine-type pneumococci and NTHi, and any OM, including any tympanic membrane perforation. Parental interviews will provide data on common risk factors for OM.

Ethics and dissemination

Ethical approval has been obtained from NT Department of Health and Menzies HREC (EC00153), Central Australian HREC (EC00155) and West Australian Aboriginal Health Ethics Committee (WAAHEC- 377-12/2011). Final trial results, data analyses, interpretation and conclusions will be presented in appropriate written and oral formats to parents and guardians, participating communities, local, national and international conferences, and published in peer-reviewed open access journals.

Trial registration numbers

ACTRN12610000544077 andNCT01174849.
Improving the quality of initial management of self harm and suicide patients in A+E at the James Paget Hospital
Authors: Cracknell Ben
Published: January 2015

Our objective was to improve the initial management and documentation of suicide risk assessment in the notes of patients attending A+E with a suicide attempt or self harm.

An initial audit was carried out in 2012 looking at the notes of 50 patients who attended the James Paget Hospital accident and emergency (A+E) department following a suicide attempt or self harm episode. Compliance to the NICE guidelines on the initial management of self harm was assessed and was found to be low in certain areas. A significant number of these patients are discharged without evidence of a satisfactory suicide risk assessment being documented. This is dangerous practice for the patients and puts the doctor at risk medico-legally.

A number of interventions were introduced to raise compliance to the NICE guidelines. These changes included adaptation to the self harm pro-forma to better conform to the NICE guidelines, departmental teaching sessions, and posters of the pro-forma put up in A+E at the doctors stations. In addition, a "see and greet" nurse was involved in the triage and administration of activated charcoal.

The audit was repeated in 2013 and 2014. It was found that the interventions led to an increase in compliance to the NICE guidelines and better documentation in the notes of patients who present with a suicide attempt or self harm episode.
Longitudinal change in quality of life following hospitalisation for acute exacerbations of COPD
Authors: Steer John , Gibson G John , Bourke Stephen C
Published: January 2015

Background

Current guidelines for management of patients hospitalised with acute exacerbations of chronic obstructive pulmonary disease (COPD) recommend that clinical decisions, including escalation to assisted ventilation, be informed by an estimate of the patients’ likely postdischarge quality of life. There is little evidence to inform predictions of outcome in terms of quality of life, psychological well-being and functional status. Undue nihilism might lead to denial of potentially life-saving therapy, while undue optimism might prolong suffering when alternative palliation would be more appropriate. This study aimed to detail longitudinal changes in quality of life following hospitalisation for acute exacerbations of COPD.

Methods

We prospectively recruited two cohorts (exacerbations requiring assisted ventilation during admission and exacerbations not ventilated). Admission clinical data, and mortality and readmission details were collected. Quality of life, psychological well-being and functional status were formally assessed over the subsequent 12 months. Time-adjusted mean change in quality of life was examined.

Results

183 patients (82 ventilated; 101 not ventilated) were recruited. On average, overall quality of life improved by a clinically important amount in those not ventilated and did not decline in ventilated patients. Both groups showed clinically important improvements in respiratory symptoms and an individual's sense of control over their condition, despite the tendency for functional status to decline.

Conclusions

On average, postdischarge quality of life improved in non-ventilated and did not decline in ventilated patients. Certain quality of life domains (ie, symptoms and mastery) improved significantly. Better understanding of longitudinal change in postdischarge quality of life should help to inform decision-making.
Short-term and long-term storage stability of heparin plasma ammonia
Authors: Dukic Lora , Simundic Ana-Maria
Published: January 2015

Aims

Ammonia is an extremely unstable analyte and requires special attention during sampling, transport and storage. The aim of this study was to evaluate the stability of ammonia in lithium-heparin plasma during short-term (at +4°C) and long-term (at −20°C) storage.

Methods

Twenty plasma samples were used for short-term stability assessment. Each sample was divided into five aliquots and stored in stoppered tubes at +4°C, for 1, 2, 3, 4 and 24 h from initial testing. Fifteen plasma samples were used for long-term stability assessment. Each sample was divided into eight aliquots and stored in stoppered tubes at −20°C for 3, 24, 48 h and 1, 2, 4, 8 and 12 weeks from initial testing. Ammonia concentration was determined on a Beckman Coulter AU2700 chemistry analyser using Randox ammonia enzymatic UV method. Bias was calculated from initial value for each time point and compared with quality specifications defined by Royal College of Pathologists of Australasia.

Results

The average bias exceeded the total allowable error after storage of samples for 1 h at +4°C and 3 h at −20°C.

Conclusion

Ammonia is not stable during storage at +4°C and −20°C in lithium-heparinised plasma and should therefore be analysed immediately.
Low IQ has become less important as a risk factor for early disability pension. A longitudinal population-based study across two decades among Swedish men
Authors: Karnehed Nina , Rasmussen Finn , Modig Karin
Published: January 2015

Background

Low IQ has been shown to be an important risk factor for disability pension (DP) but whether the importance has changed over time remains unclear. It can be hypothesised that IQ has become more important for DP over time in parallel with a more demanding working life. The aim of this study was to investigate the relative risk of low IQ on the risk of DP before age 30 between 1971 and 2006.

Methods

This study covered the entire Swedish male population born between 1951 and 1976, eligible for military conscription. Information about the study subjects was obtained by linkage of national registers. Associations between IQ and DP over time were analysed by descriptive measures (mean values, proportions, etc) and by Cox proportional hazards regressions. Analyses were adjusted for educational level.

Results

The cohort consisted of 1 229 346 men. The proportion that received DP before the age of 30 increased over time, from 0.68% in the cohort born between 1951 and 1955 to 0.95% in the cohort born between 1971 and 1976. The relative risk of low IQ (adjusted for education) in relation to high IQ decreased from 5.68 (95% CI 4.71 to 6.85) in the cohort born between 1951 and 1955 to 2.62 (95% CI 2.25 to 3.05) in the cohort born between 1971 and 1976.

Conclusions

Our results gave no support to the idea that the importance of low IQ for the risk of DP has increased in parallel with increasing demands in working life. In fact, low IQ has become less important as a risk factor for DP compared with high IQ between the early 1970s and 1990s. An increased educational level over the same time period is likely to be part of the explanation.
Current challenges in palliative care provision for heart failure in the UK: a survey on the perspectives of palliative care professionals
Authors: Cheang Mun Hong , Rose Gabrielle , Cheung Chi-Chi , Thomas Martin
Published: January 2015

Objective

Palliative care (PC) in heart failure (HF) is beneficial and recommended in international HF guidelines. However, there is a perception that PC is underutilised in HF in the UK. This exploratory study aims to investigate, from a PC perspective, this perceived underutilisation and identify problems with current practice that may impact on the provision of PC in HF throughout the UK.

Methods

A prospective survey was electronically sent to PC doctors and nurses via the UK Association for Palliative Medicine and adult PC teams listed in the UK Hospice directory.

Results

We received 499 responses (42%—PC consultants). Although PC provision for patients with HF was widespread, burden on PC services was low (47% received less than 10 referrals annually). While PC was acknowledged to have a role in end-stage HF, there were differing views about the optimal model of care. Levels of interdisciplinary collaboration (58%) and mutual education (36%) were low. There were frequent reports that end-of-life matters were not addressed by cardiology prior to PC referral. Moreover, 24% of respondents experienced difficulties with implantable cardioverter defibrillator deactivation.

Conclusions

Low HF referrals despite widespread availability of PC services and insufficient efforts by cardiology to address PC issues may contribute to the perception that PC is underutilised in HF. The challenges facing PC and HF identified here need to be further investigated and addressed. These findings will hopefully promote awareness of PC issues in HF and encourage debate on how to improve PC support for this population.
Patients with diabetes requiring emergency department care for hypoglycaemia: characteristics and long-term outcomes determined from multiple data sources
Authors: Rajendran Rajesh , Hodgkinson David , Rayman Gerry
Published: January 2015

Aim

To triangulate three data sources and report the characteristics and long-term outcomes of patients with diabetes requiring emergency department (ED) care for hypoglycaemia.

Method

Three data sources were used—ambulance electronic records, hospital episode statistics and patient administration system. Hypoglycaemia (capillary blood glucose <4.0 mmol/L)-related attendances to a single hospital's ED between 1 April 2012 and 31 March 2013 were studied.

Results

Using the three sources, there were 165 hypoglycaemia-related attendances in 132 patients with diabetes [type 1–59 episodes in 43 patients, type 2–106 episodes in 89 patients (therapy—54 (51%) insulin, 35 (33%) sulfonylurea, 11 (10%) both, 6 (6%) others)]. At best only 65% of episodes would have been identified were a single data source used. Patients with type 2 vs type 1 diabetes were older (median age 79 vs 61 years, p<0.0001), had more comorbidities (median Charlson comorbidity index (CCI) 4 vs 3, p=0.002) but no difference in HbA1c (median 7.8% vs 8.4%, p=0.065). Compared with insulin-treated type 2 patients with diabetes, sulfonylurea-treated patients (33%) were older (median age 82 vs 76 years, p=0.007), had worse renal function (median estimated glomerular filtration rate 38 vs 56 mL/min/1.73 m2, p=0.019) and lower HbA1c (median 6.7% vs 8.4%, p<0.0001). At least 17 (10%) hypoglycaemic episodes resulted in additional serious harm. The 30-day, 90-day and 1-year all-cause mortality were 10.6% (14), 16.7% (22) and 28% (37), respectively. Age, CCI and hospitalisation were risk factors for long-term mortality.

Conclusions

Dependence on a single data source would have at best identified only 65% of episodes. One-third of episodes were sulfonylurea related in patients with type 2 diabetes, and one-fourth of all patients with diabetes who required ED care for hypoglycaemia died the following year.
The Effect of Laser Wavelength and Concentration on Thermal Nonlinear Refractive Index of Graphene Suspensions
Authors: Arandian A. , Karimzadeh R. , Faizabadi S. Y.
Published: January 2015

In this work, the nonlinear refractive properties of graphene suspension at different concentration levels are investigated by means of Z-scan technique with continuous wave low power laser beams at 532 nm and 635 nm. Results show that the dispersion of graphene in water exhibits negative nonlinear refractive index in continuous wave regime, which is mainly attributed to thermal nonlinear effect. We find that the absorption coefficient and nonlinear refractive index of the samples increase with increasing the concentration level of the graphene. Moreover, it is obtained that the nonlinear refractive index of the samples at different concentration levels depends on the wavelength of laser beam.
Human Development Status and Regional Disparity in China
Authors: ZHANG Ying , ZHANG Bin
Published: January 2015

The 2010 United Nations Development Programme (UNDP) Global Human Development Report introduced a new methodology to calculate Human Development Index (HDI). Three dimensions of HDI i.e. income, education, and health are adjusted for inequalities in attainments across people. The paper uses the new methodology to estimate 2010 China's national and provincial HDI. Compared with UNDP global report, all the data used here are from China's domestic sources. The education indicator estimated here by referring to detailed local statistics and documents are higher than that in UNDP's global report, thus contributing a slight higher overall HDI estimate. Based on the estimation results here and UNDP's report, China is located in between high human development and low human development, in other words, placed around the half position among all 169 countries. To facilitate a cross-country comparison, the indices are normalized with reference to the goalposts outlined in the HDR 2010. When ranked according to global goalposts, Beijing's rank is 31 whereas the least developed Tibet only ranks 114. Most of the regional disparity is driven by their income differences. The findings of this paper try to shed light on the status of China's human development and also gain insights on China's regional disparity. Further research is required to explore the inter-linkages between inequalities across various dimensions and to examine the factors behind these inequalities.
TAM Receptor Signaling in Immune Homeostasis
Authors: Rothlin Carla V. , Carrera-Silva Eugenio A. , Bosurgi Lidia , Ghosh Sourav
Published: January 2015

The TAM receptor tyrosine kinases (RTKs)—TYRO3, AXL, and MERTK—together with their cognate agonists GAS6 and PROS1 play an essential role in the resolution of inflammation. Deficiencies in TAM signaling have been associated with chronic inflammatory and autoimmune diseases. Three processes regulated by TAM signaling may contribute, either independently or collectively, to immune homeostasis: the negative regulation of the innate immune response, the phagocytosis of apoptotic cells, and the restoration of vascular integrity. Recent studies have also revealed the function of TAMs in infectious diseases and cancer. Here, we review the important milestones in the discovery of these RTKs and their ligands and the studies that underscore the functional importance of this signaling pathway in physiological immune settings and disease.
Low-Temperature Kinetics and Dynamics with Coulomb Crystals
Authors: Heazlewood Brianna R. , Softley Timothy P.
Published: January 2015

Coulomb crystals—as a source of translationally cold, highly localized ions—are being increasingly utilized in the investigation of ion-molecule reaction dynamics in the cold regime. To develop a fundamental understanding of ion-molecule reactions, and to challenge existing models that describe the rates, product branching ratios, and temperature dependence of such processes, investigators need to exercise full control over the experimental reaction parameters. This requires not only state selection of the reactants, but also control over the collision process (e.g., the collisional energy and angular momentum) and state-selective product detection. The combination of Coulomb crystals in ion traps with cold neutral-molecule sources is enabling the measurement of state-selective reaction rates in a diverse range of systems. With the development of appropriate product detection techniques, we are moving toward the ultimate goal of examining low-energy, state-to-state ion-molecule reaction dynamics.
Mass Spectrometry of Protein Complexes: From Origins to Applications
Authors: Mehmood Shahid , Allison Timothy M. , Robinson Carol V.
Published: January 2015

Now routine is the ability to investigate soluble and membrane protein complexes in the gas phase of a mass spectrometer while preserving folded structure and ligand-binding properties. Several recent transformative developments have occurred to arrive at this point. These include advances in mass spectrometry instrumentation, particularly with respect to resolution; the ability to study intact membrane protein complexes released from detergent micelles; and the use of protein unfolding in the gas phase to obtain stability parameters. Together, these discoveries are providing unprecedented information on the compositional heterogeneity of biomacromolecules, the unfolding trajectories of multidomain proteins, and the stability imparted by ligand binding to both soluble and membrane-embedded protein complexes. We review these recent breakthroughs, highlighting the challenges that had to be overcome and the physicochemical insight that can now be gained from studying proteins and their assemblies in the gas phase.
The Politics of Central Bank Independence
Authors: Fernández-Albertos José
Published: January 2015

This article reviews recent contributions addressing the following questions: Under what circumstances is monetary policy delegated to politically independent central banks? What effects do these politically independent institutions have, and how do they interact with their macroeconomic institutional environment? What explains the variation in their behavior? And finally, to what extent has the recent economic crisis altered the role of these institutions? In answering these questions, this article advances two arguments. First, even though central banks' activities involve a great deal of technical knowledge, they are unavoidably political institutions: They make distributional choices informed by ideas, preferences, and the political context in which they operate. Second, the economic crisis, by expanding the type of activities that monetary authorities undertake, further contributes to the politicization of these institutions. The final section of the article speculates about the implications of these developments for economic policy making in contemporary democracies.
Has Epidemiology Become Infatuated With Methods? A Historical Perspective on the Place of Methods During the Classical (1945–1965) Phase of Epidemiology
Authors: Morabia Alfredo
Published: January 2015

Before World War II, epidemiology was a small discipline, practiced by a handful of people working mostly in the United Kingdom and in the United States. Today it is practiced by tens of thousands of people on all continents. Between 1945 and 1965, during what is known as its “classical” phase, epidemiology became recognized as a major academic discipline in medicine and public health. On the basis of a review of the historical evidence, this article examines to which extent classical epidemiology has been a golden age of an action-driven, problem-solving science, in which epidemiologists were less concerned with the sophistication of their methods than with the societal consequences of their work. It also discusses whether the paucity of methods stymied or boosted classical epidemiology's ability to convince political and financial agencies about the need to intervene in order to improve the health of the people.
Impaired dynamic cerebral autoregulation at rest and during isometric exercise in type 2 diabetes patients
Authors: Vianna Lauro C. , Deo Shekhar H. , Jensen Areum K. , Holwerda Seth W. , Zimmerman Matthew C. , Fadel Paul J.
Published: January 2015

Type 2 diabetes mellitus patients (T2D) have elevated risk of stroke, suggesting that cerebrovascular function is impaired. Herein, we examined dynamic cerebral autoregulation (CA) at rest and during exercise in T2D patients and determined whether underlying systemic oxidative stress is associated with impairments in CA. Middle cerebral artery blood velocity and arterial blood pressure (BP) were measured at rest and during 2-min bouts of low- and high-intensity isometric handgrip performed at 20% and 40% maximum voluntary contraction, respectively, in seven normotensive and eight hypertensive T2D patients and eight healthy controls. Dynamic CA was estimated using the rate of regulation (RoR). Total reactive oxygen species (ROS) and superoxide levels were measured at rest. There were no differences in RoR at rest or during exercise between normotensive and hypertensive T2D patients. However, when compared with controls, T2D patients exhibited lower RoR at rest and during low-intensity handgrip indicating impaired dynamic CA. Moreover, the RoR was further reduced by 29 ± 4% during high-intensity handgrip in T2D patients (0.307 ± 0.012/s rest vs. 0.220 ± 0.014/s high intensity; P < 0.01), although well maintained in controls. T2D patients demonstrated greater baseline total ROS and superoxide compared with controls, both of which were negatively related to RoR during handgrip (e.g., total ROS: r = −0.71, P < 0.05; 40% maximum voluntary contraction). Collectively, these data demonstrate impaired dynamic CA at rest and during isometric handgrip in T2D patients, which may be, in part, related to greater underlying systemic oxidative stress. Additionally, dynamic CA is blunted further with high intensity isometric contractions potentially placing T2D patients at greater risk for cerebral events during such activities.
Transglutaminase activity is decreased in large arteries from hypertensive rats compared with normotensive controls
Authors: Petersen-Jones Humphrey G. , Johnson Kyle B. , Hitomi Kiyotaka , Tykocki Nathan R. , Thompson Janice M. , Watts Stephanie W.
Published: January 2015

Transglutaminases (TGs) catalyze the formation of covalent cross-links between glutamine residues and amine groups. This cross-linking activity has been implicated in arterial remodeling. Because hypertension is characterized by arterial remodeling, we hypothesized that TG activity, expression, and functionality would be increased in the aorta, but not in the vena cava (which does not undergo remodeling), from hypertensive rats relative to normotensive rats. Spontaneously hypertensive stroke-prone rats (SHRSP) and DOCA-salt rats as well as their respective normotensive Wistar-Kyoto or Sprague-Dawley counterparts were used. Immunohistochemistry and Western blot analysis measured the presence and expression of TG1 and TG2, in situ activity assays quantified active TGs, and isometric contractility was used to measure TG functionality. Contrary to our hypothesis, the activity (52% DOCA-salt vs. control rats and 56% SHRSP vs. control rats, P < 0.05), expression (TG1: 54% DOCA-salt vs. control rats, P > 0.05, and TG2: 77% DOCA-salt vs. control rats, P < 0.05), and functionality of TG1 and TG2 were decreased in the aorta, but not in the vena cava, from hypertensive rats. Mass spectrometry identified proteins uniquely amidated by TGs in the aorta that play roles in cytoskeletal regulation, redox regulation, and DNA/RNA/protein synthesis and regulation and in the vena cava that play roles in cytoskeletal regulation, coagulation regulation, and cell metabolism. Consistent with the idea that growing cells lose TG2 expression, vascular smooth muscle cells placed in culture lost TG2 expression. We conclude that the expression, activity, and functionality of TG1 and TG2 are decreased in the aorta, but not in the vena cava, from hypertensive rats compared with control rats.
Cardiac tissue slices: preparation, handling, and successful optical mapping
Authors: Wang Ken , Lee Peter , Mirams Gary R. , Sarathchandra Padmini , Borg Thomas K. , Gavaghan David J. , Kohl Peter , Bollensdorff Christian
Published: January 2015

Cardiac tissue slices are becoming increasingly popular as a model system for cardiac electrophysiology and pharmacology research and development. Here, we describe in detail the preparation, handling, and optical mapping of transmembrane potential and intracellular free calcium concentration transients (CaT) in ventricular tissue slices from guinea pigs and rabbits. Slices cut in the epicardium-tangential plane contained well-aligned in-slice myocardial cell strands (“fibers”) in subepicardial and midmyocardial sections. Cut with a high-precision slow-advancing microtome at a thickness of 350 to 400 μm, tissue slices preserved essential action potential (AP) properties of the precutting Langendorff-perfused heart. We identified the need for a postcutting recovery period of 36 min (guinea pig) and 63 min (rabbit) to reach 97.5% of final steady-state values for AP duration (APD) (identified by exponential fitting). There was no significant difference between the postcutting recovery dynamics in slices obtained using 2,3-butanedione 2-monoxime or blebistatin as electromechanical uncouplers during the cutting process. A rapid increase in APD, seen after cutting, was caused by exposure to ice-cold solution during the slicing procedure, not by tissue injury, differences in uncouplers, or pH-buffers (bicarbonate; HEPES). To characterize intrinsic patterns of CaT, AP, and conduction, a combination of multipoint and field stimulation should be used to avoid misinterpretation based on source-sink effects. In summary, we describe in detail the preparation, mapping, and data analysis approaches for reproducible cardiac tissue slice-based investigations into AP and CaT dynamics.
Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload
Authors: Yancey Danielle M. , Guichard Jason L. , Ahmed Mustafa I. , Zhou Lufang , Murphy Michael P. , Johnson Michelle S. , Benavides Gloria A. , Collawn James , Darley-Usmar Victor , Dell'Italia Louis J.
Published: January 2015

Left ventricular (LV) volume overload (VO) results in cardiomyocyte oxidative stress and mitochondrial dysfunction. Because mitochondria are both a source and target of ROS, we hypothesized that the mitochondrially targeted antioxidant mitoubiquinone (MitoQ) will improve cardiomyocyte damage and LV dysfunction in VO. Isolated cardiomyocytes from Sprague-Dawley rats were exposed to stretch in vitro and VO of aortocaval fistula (ACF) in vivo. ACF rats were treated with and without MitoQ. Isolated cardiomyocytes were analyzed after 3 h of cyclical stretch or 8 wk of ACF with MitoSox red or 5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate to measure ROS and with tetramethylrhodamine to measure mitochondrial membrane potential. Transmission electron microscopy and immunohistochemistry were used for cardiomyocyte structural assessment. In vitro cyclical stretch and 8-wk ACF resulted in increased cardiomyocyte mitochondrial ROS production and decreased mitochondrial membrane potential, which were significantly improved by MitoQ. ACF had extensive loss of desmin and β2-tubulin that was paralleled by mitochondrial disorganization, loss of cristae, swelling, and clustering identified by mitochondria complex IV staining and transmission electron microscopy. MitoQ improved mitochondrial structural damage and attenuated desmin loss/degradation evidenced by immunohistochemistry and protein expression. However, LV dilatation and fractional shortening were unaffected by MitoQ treatment in 8-wk ACF. In conclusion, although MitoQ did not affect LV dilatation or function in ACF, these experiments suggest a connection of cardiomyocyte mitochondria-derived ROS production with cytoskeletal disruption and mitochondrial damage in the VO of ACF.
Gene transfer of cystathionine β-synthase into RVLM increases hydrogen sulfide-mediated suppression of sympathetic outflow via KATP channel in normotensive rats
Authors: Duan Xiao-cui , Guo Rong , Liu Shang-yu , Xiao Lin , Xue Hong-mei , Guo Qi , Jin Sheng , Wu Yu-ming
Published: January 2015

Hydrogen sulfide has been shown to have a sympathoinhibitory effect in the rostral ventrolateral medulla (RVLM). The present study examined the function of cystathionine β-synthase (CBS)/hydrogen sulfide system in the RVLM, which plays a crucial role in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding CBS (AdCBS) or enhanced green fluorescent protein (AdEGFP) were transfected into the RVLM in normotensive rats. Identical microinjection of AdCBS into the RVLM had no effect on systolic blood pressure and heart rate (HR) in conscious rats. Acute experiments were performed at day 7 after gene transfer in anesthetized rats. Microinjection of the CBS inhibitors hydroxylamine (HA) or amino-oxyacetate into the RVLM produced an increase in the renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and HR. There was a potentiation of the increases in RSNA, MAP, and HR because of the CBS inhibitors in AdCBS-injected rats compared with AdEGFP-injected rats. Pretreatment with pinacidil, a ATP-sensitive potassium (KATP) channel activator, abolished the effects of HA in two groups. Microinjection of glibenclamide, a KATP channel blocker, produced increases in RSNA, MAP, and HR in AdCBS-injected rats. No changes in behavior were observed in AdEGFP-injected rats. Furthermore, Western blot analysis indicated an increase in the expression of sulfonylurea receptor 2 and inward rectifier K+ 6.1 in AdCBS-injected rats. These results suggest that the increase in KATP channels in the RVLM may be responsible for the greater sympathetic outflow and pressor effect of HA in AdCBS-injected rats compared with AdEGFP-injected rats.
Carbon monoxide increases inducible NOS expression that mediates CO-induced myocardial damage during ischemia-reperfusion
Authors: Meyer Grégory , André Lucas , Kleindienst Adrien , Singh François , Tanguy Stéphane , Richard Sylvain , Obert Philippe , Boucher François , Jover Bernard , Cazorla Olivier , Reboul Cyril
Published: January 2015

We investigated the role of inducible nitric oxide (NO) synthase (iNOS) on ischemic myocardial damage in rats exposed to daily low nontoxic levels of carbon monoxide (CO). CO is a ubiquitous environmental pollutant that impacts on mortality and morbidity from cardiovascular diseases. We have previously shown that CO exposure aggravates myocardial ischemia-reperfusion (I/R) injury partly because of increased oxidative stress. Nevertheless, cellular mechanisms underlying cardiac CO toxicity remain hypothetical. Wistar rats were exposed to simulated urban CO pollution for 4 wk. First, the effects of CO exposure on NO production and NO synthase (NOS) expression were evaluated. Myocardial I/R was performed on isolated perfused hearts in the presence or absence of S-methyl-isothiourea (1 μM), a NOS inhibitor highly specific for iNOS. Finally, Ca2+handling was evaluated in isolated myocytes before and after an anoxia-reoxygenation performed with or without S-methyl-isothiourea or N-acetylcystein (20 μM), a nonspecific antioxidant. Our main results revealed that 1) CO exposure altered the pattern of NOS expression, which is characterized by increased neuronal NOS and iNOS expression; 2) cardiac NO production increased in CO rats because of its overexpression of iNOS; and 3) the use of a specific inhibitor of iNOS reduced myocardial hypersensitivity to I/R (infarct size, 29 vs. 51% of risk zone) in CO rat hearts. These last results are explained by the deleterious effects of NO and reactive oxygen species overproduction by iNOS on diastolic Ca2+overload and myofilaments Ca2+sensitivity. In conclusion, this study highlights the involvement of iNOS overexpression in the pathogenesis of simulated urban CO air pollution exposure.
Inspiratory resistive breathing induces MMP-9 and MMP-12 expression in the lung
Authors: Toumpanakis Dimitrios , Noussia Olga , Sigala Ioanna , Litsiou Eleni , Loverdos Konstantinos , Zacharatos Panagiotis , Karavana Vassiliki , Michailidou Tatiana , Magkou Christina , Zhou Zongmin , Theocharis Stamatios , Vassilakopoulos Theodoros
Published: January 2015

Inspiratory resistive breathing (IRB) is characterized by large negative intrathoracic pressures and was shown to induce pulmonary inflammation in previously healthy rats. Matrix metalloproteinases (MMP)-9 and -12 are induced by inflammation and mechanical stress in the lung. We hypothesized that IRB induces MMP-9 and -12 in the lung. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve, connected to an inspiratory resistance, with the tidal inspiratory tracheal pressure set at 50% of the maximum. Quietly breathing animals served as controls. After 3 and 6 h of IRB, respiratory mechanics were measured, bronchoalveolar lavage (BAL) was performed, lung injury score was estimated, and lung MMP-9 was estimated by zymography and ELISA. MMP-9 and MMP-12 immunohistochemistry was performed. Isolated normal alveolar macrophages were incubated with BAL from rats that underwent IRB. After 18 h, MMP-9 and -12 levels were measured in supernatants, and immunocytochemistry was performed. Macrophages were treated with IL-1β, IL-6, or TNF-α, and MMP-9 in supernatants was measured. After 6 h of IRB, leukocytes in BAL increased, and IL-1β and IL-6 levels were elevated. Elasticity and injury score were increased after 3 and 6 h of IRB. Lung MMP-9 levels increased after 6 h of IRB. MMP-9 and MMP-12 were detected in alveolar macrophages and epithelial (bronchial/alveolar) cells after 3 and 6 h of IRB. MMP-9 and MMP-12 were found in supernatants after treatment with 6 h of IRB BAL. Cytosolic immunostaining was detected after treatment with 3 and 6 h of IRB BAL. All cytokines induced MMP-9 in culture supernatants. In conclusion, IRB induces MMP-9 and -12 in the lung of previously healthy rats.
Alcohol-induced ciliary dysfunction targets the outer dynein arm
Authors: Yang Fan , Pavlik Jacqueline , Fox Laura , Scarbrough Chasity , Sale Winfield S. , Sisson Joseph H. , Wirschell Maureen
Published: January 2015

Alcohol abuse results in an increased incidence of pulmonary infection, in part attributable to impaired mucociliary clearance. Analysis of motility in mammalian airway cilia has revealed that alcohol impacts the ciliary dynein motors by a mechanism involving altered axonemal protein phosphorylation. Given the highly conserved nature of cilia, it is likely that the mechanisms for alcohol-induced ciliary dysfunction (AICD) are conserved. Thus we utilized the experimental advantages offered by the model organism, Chlamydomonas, to determine the precise effects of alcohol on ciliary dynein activity and identify axonemal phosphoproteins that are altered by alcohol exposure. Analysis of live cells or reactivated cell models showed that alcohol significantly inhibits ciliary motility in Chlamydomonas via a mechanism that is part of the axonemal structure. Taking advantage of informative mutant cells, we found that alcohol impacts the activity of the outer dynein arm. Consistent with this finding, alcohol exposure results in a significant reduction in ciliary beat frequency, a parameter of ciliary movement that requires normal outer dynein arm function. Using mutants that lack specific heavy-chain motor domains, we have determined that alcohol impacts the β- and γ-heavy chains of the outer dynein arm. Furthermore, using a phospho-threonine-specific antibody, we determined that the phosphorylation state of DCC1 of the outer dynein arm-docking complex is altered in the presence of alcohol, and its phosphorylation correlates with AICD. These results demonstrate that alcohol targets specific outer dynein arm components and suggest that DCC1 is part of an alcohol-sensitive mechanism that controls outer dynein arm activity.
Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor
Authors: Leuchte Hanno H. , Prechtl Christoph , Callegari Jens , Meis Tobias , Haziraj Shani , Bevec Dorian , Behr Jürgen
Published: January 2015

A deficiency of the pulmonary vasodilative vasoactive intestinal peptide (VIP) has been suggested to be involved in the pathophysiology of pulmonary hypertension (PH). Supplementation of VIP as an aerosol is hampered by the fact that it is rapidly inactivated by neutral endopeptidases (NEP) located on the lung surface. Coapplication of thiorphan, an NEP 24.11 inhibitor, could augment the biological effects of inhaled VIP alone. A stable pulmonary vasoconstriction with a threefold increase of pulmonary artery pressure was established by application the thromboxane mimetic U46619 in the isolated rabbit lung model. VIP and thiorphan were either applied intravascularly or as an aerosol. VIP caused a significant pulmonary vasodilation either during intravascular application or inhalation. These effects were of short duration. Thiorphan application had no effects on pulmonary vasoconstriction per se but significantly augmented the effects of VIP aerosol. Thiorphan, not only augmented the maximum hemodynamic effects of VIP aerosol, but also led to a significant prolongation of these effects. VIP causes pulmonary vasodilation in a model of acute experimental PH. The hemodynamic effects of VIP aerosol can be significantly augmented via coapplication of an NEP inhibitor.
Edible Mushrooms: Improving Human Health and Promoting Quality Life
Authors: Valverde María Elena , Hernández-Pérez Talía , Paredes-López Octavio
Published: January 2015

Mushrooms have been consumed since earliest history; ancient Greeks believed that mushrooms provided strength for warriors in battle, and the Romans perceived them as the “Food of the Gods.” For centuries, the Chinese culture has treasured mushrooms as a health food, an “elixir of life.” They have been part of the human culture for thousands of years and have considerable interest in the most important civilizations in history because of their sensory characteristics; they have been recognized for their attractive culinary attributes. Nowadays, mushrooms are popular valuable foods because they are low in calories, carbohydrates, fat, and sodium: also, they are cholesterol-free. Besides, mushrooms provide important nutrients, including selenium, potassium, riboflavin, niacin, vitamin D, proteins, and fiber. All together with a long history as food source, mushrooms are important for their healing capacities and properties in traditional medicine. It has reported beneficial effects for health and treatment of some diseases. Many nutraceutical properties are described in mushrooms, such as prevention or treatment of Parkinson, Alzheimer, hypertension, and high risk of stroke. They are also utilized to reduce the likelihood of cancer invasion and metastasis due to antitumoral attributes. Mushrooms act as antibacterial, immune system enhancer and cholesterol lowering agents; additionally, they are important sources of bioactive compounds. As a result of these properties, some mushroom extracts are used to promote human health and are found as dietary supplements.
Massive Cerebral Gas Embolism under Discectomy due to Hydrogen Peroxide Irrigation
Authors: Zhang Junjie , Zhang Chengliang , Yan Jianqin
Published: January 2015

Massive cerebral and spinal gas embolism occurs rarely as a complication of discectomy. We report a 54-year-old female who had undergone a discectomy (L3/4 and L4/5) under epidural anesthesia in a local hospital developed multiple massive gas embolisms. At closure, surgeons irrigated the incision wound with hydrogen peroxide. Soon after the irrigation, the patient suddenly developed tachycardia, hypotension, and rapid oxygen desaturation. Subsequently, patient progressed into unconsciousness and right hemianopsia quadriplegia. Computed tomography (CT) scan showed multiple hypointensity spots around the brain due to cerebral gas embolism, which indicated the pneumoencephalos. The likely mechanism was the absorption of hydrogen peroxide into blood. When the amount of oxygen evolved exceeded its maximal blood solubility, venous embolization occurred. Though the patient was treated with supportive treatments and hyperbaric oxygen, she did not get full recovery and was left with severe long-term cerebral injury.
Analysis of a Multiserver Queueing-Inventory System
Authors: Krishnamoorthy A. , Manikandan R. , Shajin Dhanya
Published: January 2015

We attempt to derive the steady-state distribution of theM/M/cqueueing-inventory system with positive service time. First we analyze the case ofc=2servers which are assumed to be homogeneous and that the service time follows exponential distribution. The inventory replenishment follows the(s,Q)policy. We obtain a product form solution of the steady-state distribution under the assumption that customers do not join the system when the inventory level is zero. An average system cost function is constructed and the optimal pair(s,Q)and the corresponding expected minimum cost are computed. As in the case ofM/M/cretrial queue withc≥3, we conjecture thatM/M/cforc≥3, queueing-inventory problems, do not have analytical solution. So we proceed to analyze such cases using algorithmic approach. We derive an explicit expression for the stability condition of the system. Conditional distribution of the inventory level, conditioned on the number of customers in the system, and conditional distribution of the number of customers, conditioned on the inventory level, are derived. The distribution of two consecutivestostransitions of the inventory level (i.e., the first return time tos) is computed. We also obtain several system performance measures.
Alterations Induced by Bangerter Filters on the Visual Field: A Frequency Doubling Technology and Standard Automated Perimetry Study
Authors: Schiavi Costantino , Tassi Filippo , Finzi Alessandro , Cellini Mauro
Published: January 2015

Purpose. To investigate the effects of Bangerter filters on the visual field in healthy and in amblyopic patients.Materials and Methods. Fifteen normal adults and fifteen anisometropic amblyopia patients were analysed with standard automated perimetry (SAP) and frequency doubling technology (FDT) at baseline and with filters 0.8 and 0.1.Results. With 0.1 filter in SAP there was an increase of MD compared with controls (−10.24 ± 1.09 dB) in either the amblyopic (−11.34 ± 2.06 dB;P<0.050) or sound eyes (−11.34 ± 1.66 dB;P<0.030). With filters 0.8 the PSD was increased in the amblyopic eyes (2.09 ± 0.70 dB;P<0.007) and in the sound eyes (1.92 ± 0.29 dB;P<0.004) compared with controls. The FDT-PSD values in the control group were increased with the interposition of the filters compared to baseline (0.8;P<0.0004and 0.1;P<0.0010). We did not find significant differences of the baseline PSD between amblyopic eyes (3.80 ± 2.21 dB) and the sound eyes (4.33 ± 1.31 dB) and when comparing the filters 0.8 (4.55 ± 1.50 versus 4.53 ± 1.76 dB) and 0.1 (4.66 ± 1.80 versus 5.10 ± 2.04 dB).Conclusions. The use of Bangerter filters leads to a reduction of the functionality of the magno- and parvocellular pathway.
ERBB3-Independent Activation of the PI3K Pathway in EGFR-Mutant Lung Adenocarcinomas
Authors: Song Xiaoling , Fan Pang-Dian , Bantikassegn Amlak , Guha Udayan , Threadgill David W. , Varmus Harold , Politi Katerina
Published: January 2015

ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3K–AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFRL858R-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications. Cancer Res; 75(6); 1035–45. ©2015 AACR.
Tumorigenic Activity of Merkel Cell Polyomavirus T Antigens Expressed in the Stratified Epithelium of Mice
Authors: Spurgeon Megan E. , Cheng Jingwei , Bronson Roderick T. , Lambert Paul F. , DeCaprio James A.
Published: January 2015

Merkel cell polyomavirus (MCPyV) is frequently associated with Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine skin cancer. Most MCC tumors contain integrated copies of the viral genome with persistent expression of the MCPyV large T (LT) and small T (ST) antigen. MCPyV isolated from MCC typically contains wild-type ST but truncated forms of LT that retain the N-terminus but delete the C-terminus and render LT incapable of supporting virus replication. To determine the oncogenic activity of MCC tumor-derived T antigens in vivo, a conditional, tissue-specific mouse model was developed. Keratin 14-mediated Cre recombinase expression induced expression of MCPyV T antigens in stratified squamous epithelial cells and Merkel cells of the skin epidermis. Mice expressing MCPyV T antigens developed hyperplasia, hyperkeratosis, and acanthosis of the skin with additional abnormalities in whisker pads, footpads, and eyes. Nearly half of the mice also developed cutaneous papillomas. Evidence for neoplastic progression within stratified epithelia included increased cellular proliferation, unscheduled DNA synthesis, increased E2F-responsive genes levels, disrupted differentiation, and presence of a DNA damage response. These results indicate that MCPyV T antigens are tumorigenic in vivo, consistent with their suspected etiologic role in human cancer. Cancer Res; 75(6); 1068–79. ©2015 AACR.