bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing and validating a novel multisource comorbidity score from administrative data: a large population-based cohort study from Italy
Authors: Corrao Giovanni , Rea Federico , Di Martino Mirko , De Palma Rossana , Scondotto Salvatore , Fusco Danilo , Lallo Adele , Belotti Laura Maria Beatrice , Ferrante Mauro , Pollina Addario Sebastiano , Merlino Luca , Mancia Giuseppe , Carle Flavia
Published: December 2017

Objective

To develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases.

Methods

An index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated.

Results

Primary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily.

Conclusion

MCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice.
Power supplies and equipment for military field research: lessons from the British Service Dhaulagiri Research Expedition 2016
Authors: Howard Matt , Bakker-Dyos J , Gallagher L , O’Hara J P , Woods D , Mellor A
Published: December 2017

Introduction

The British Service Dhaulagiri Research Expedition (BSDMRE) took place from 27 March to 31 May 2016. The expedition involved 129 personnel, with voluntary participation in nine different study protocols. Studies were conducted in three research camps established at 3600, 4600 and 5140 m and involved taking and storing blood samples, cardiac echocardiography and investigations involving a balance plate. Research in this remote environment requires careful planning in order to provide a robust and resilient power plan. In this paper we aim to report the rationale for the choices we made in terms of power supply, the equipment used and potential military applicability.

Methods

This is a descriptive account from the expedition members involved in planning and conducting the medical research.

Results

Power calculations were used to determine estimates of requirement prior to the expedition. The primary sources used to generate power were internal combustion engine (via petrol fuelled electric generators) and solar panels. Having been generated, power was stored using lithium-ion batteries. Special consideration was given to the storage of samples taken in the field, for which electric freezers and dry shippers were used. All equipment used functioned well during the expedition, with the challenges of altitude, temperature and transport all overcome due to extensive prior planning.

Conclusions

Power was successfully generated, stored and delivered during the BSDMRE, allowing extensive medical research to be undertaken. The challenges faced and overcome are directly applicable to delivering military medical care in austere environments, and lessons learnt can help with the planning and delivery of future operations, training exercises or expeditions.
UK Role 4 military infectious diseases and tropical medicine cases in 2005–2013
Authors: Burns Daniel S , Riley M R , Mason A , Bailey M S
Published: December 2017

Introduction

Infectious diseases are a frequent cause of morbidity among British troops. The aim of this paper is to describe the spectrum of infectious diseases seen when UK service personnel are evacuated for definitive care to the Role 4 Medical Treatment Facility based at Birmingham Heartlands Hospital.

Method

A retrospective analysis of all military patients presenting with infectious diseases and treated at Birmingham Heartlands Hospital between 14 April 2005 and 31 December 2013 was undertaken.

Results

During this period, 502 patients were identified. Infections originated in 49 countries, most commonly Afghanistan (46% cases), the UK (10% cases) and Belize (9% of cases). The most common presentations were dermatological conditions, gastroenterological illnesses and undifferentiated fevers.

Conclusion

UK service personnel in significant numbers continue to suffer a wide range of infectious diseases, acquired throughout the globe, which often require specialist tertiary infection services to diagnose and manage. Future prospective data collection is recommended to identify trends, which in turn will inform military training needs and future research priorities in the Defence Medical Services (DMS) and allows development of appropriate policies and clinical guidelines for management of DMS personnel with infectious diseases.
Revenue Share Contract Design with Marketing Strategy Types of Supplier
Authors: He Hua , Ma Changsong
Published: December 2017

In this paper, we design a revenue share contract when a supplier is the leader and a retailer is the follower in a two-echelon supply chain. The innovation lies in dividing the supplier’s marketing strategies into two types: the profit oriented and the sales oriented to distinguish the different decision objectives from previous literatures assuming the supplier and retailer are both profit oriented. The paper uses the revenue share contract to reach supply chain coordination and Pareto optimality in the supply chain with the profit-oriented suppliers. However, the contract makes supply chain collaboration solutions and the Pareto improvement with the sales oriented supplier conditional. Numerical examples are given to illustrate these cases.
Holography and the conformal window in the Veneziano limit
Authors: Järvinen M.
Published: December 2017

We discuss holographic QCD in the Veneziano limit (the V-QCD models), concentrating on phenomena near the “conformal” phase transition taking place at a critical value of the ratio [Formula: see text]. In particular, we review the results for the S-parameter, the technidilaton, and the masses of the mesons.
Gauge/gravity duality — From lattice gauge theory to black hole
Authors: Kadoh Daisuke
Published: December 2017

The duality conjecture states that [Formula: see text]-dimensional maximally supersymmetric Yang–Mills theory at finite temperature is expected to be dual to the non extremal black [Formula: see text]-brane at large N. We perform the lattice simulations of SYM for [Formula: see text] to investigate the validity of the conjecture. We show that the conjecture is qualitatively valid by comparing lattice results of the black [Formula: see text]-branes mass with analytic expectations in the gravity side.
Higgs mass in D-term triggered dynamical SUSY breaking
Authors: Maru Nobuhito
Published: December 2017

We discuss a new mechanism of D-term dynamical supersymmetry breaking in the context of Dirac gaugino scenario. The existence of a nontrivial solution of the gap equation for D-term is shown. It is also shown that an observed 126 GeV Higgs mass is realized by tree level D-term effects in a broad range of parameters.
The jet energy profile: A BSM analysis tool
Authors: Chivukula R. S. , Simmons E. H. , Vignaroli N.
Published: December 2017

A new heavy di-jet resonance could be discovered at the 14 TeV LHC. In this talk we present a strategy to reveal the nature of such a particle; in particular to discern whether it is a quark–antiquark [Formula: see text], quark–gluon [Formula: see text], or gluon–gluon [Formula: see text] resonance. The strategy is based on the study of the energy profiles of the two leading jets in the di-jet channel. Including statistical uncertainties in the signal and the QCD backgrounds, we show that one can distinguish between [Formula: see text], [Formula: see text], and [Formula: see text] resonances; an evaluation of systematic uncertainties in the measurement of the jet energy profile will require a detailed detector study once sufficient 14 TeV di-jet data is in hand.
A symmetry breaking mechanism by parity assignment in the noncommutative Higgs model
Authors: Yang Masaki J. S.
Published: December 2017

We apply the orbifold grand unified theory (GUT) mechanism to the noncommutative Higgs model. An assignment of [Formula: see text] parity to the “constituent fields” induces parity assignments of both the gauge and Higgs bosons, because these bosons are treated as some kind of composite fields in this formalism.
Topology, the meson spectrum and the scalar glueball: Three probes of conformality and the way it is lost
Authors: Pallante E.
Published: December 2017

We discuss properties of non-Abelian gauge theories that change significantly across the lower edge of the conformal window. Their probes are the topological observables, the meson spectrum and the scalar glueball operator. The way these quantities change tells about the way conformal symmetry is lost.
DOES MOTIVATION AFFECT THE PERFORMANCE IN CLINICAL TESTS OF ENDURANCE OF DEEP NECK FLEXORS?
Authors: Dimitriadis Zacharias , Fragkakis Vasileios , Kapreli Eleni , Strimpakos Nikolaos , Petta Georgia
Published: December 2017

The aim of the study was to investigate the association between the performance in two clinical tests for the endurance of deep neck flexors [Craniocervical Flexion Test (CCFT) and Chin Tuck Neck Flexion Test (CTNFT)] and the motivation of participants to continue and complete physical activities. Twenty-one healthy volunteers participated (men/women 13/8, age 21.1[Formula: see text][Formula: see text][Formula: see text]1.37 years). Participants were asked to complete the Assessment Scale for Completion of Usual Physical Activities (ASCUPA), the Short Scale of Physical Activity Motives (SSPAM), a visual analog scale for the recording of their motivation to complete a physical activity (VAS motivation) and then they performed the CCFT and CTNFT. The CCFT did not present any significant correlation with either VAS motivation or ASCUPA. The CTNFT was not significantly associated with VAS motivation, but it was significantly correlated with ASCUPA ([Formula: see text], [Formula: see text]). Furthermore, the CTNFT was significantly correlated with the total number of motives for physical activity ([Formula: see text]). The correlation between the performance of the two tests was not significant ([Formula: see text], [Formula: see text]). The findings suggest that only the CTNFT is dependent on participants’ motivation to complete an activity.
Mean field dynamics of a Wilson–Cowan neuronal network with nonlinear coupling term
Authors: MacLaurin James , Salhi Jamil , Toumi Salwa
Published: December 2017

In this paper we prove the propagation of chaos property for an ensemble of interacting neurons subject to independent Brownian noise. The propagation of chaos property means that in the large network size limit, the neurons behave as if they are probabilistically independent. The model for the internal dynamics of the neurons is taken to be that of Wilson and Cowan, and we consider there to be multiple different populations. The synaptic connections are modeled with a nonlinear “electrical” model. The nonlinearity of the synaptic connections means that our model lies outside the scope of classical propagation of chaos results. We obtain the propagation of chaos result by taking advantage of the fact that the mean-field equations are Gaussian, which allows us to use Borell’s Inequality to prove that its tails decay exponentially.
Homothetic Ricci collineations in non-static plane symmetric spacetimes with perfect fluid matter
Authors: Hussain Tahir , Akhtar Sumaira Saleem
Published: December 2017

In this paper, we investigate homothetic Ricci collineations (HRCs) for non-static plane symmetric spacetimes. The source of the energy–momentum tensor is assumed to be a perfect fluid. Both degenerate as well as non-degenerate cases are considered and the HRC equations are solved in different cases. It is concluded that these spacetimes may possess 6, 7, 8, 10 or 11 HRCs in non-degenerate case, while they admit seven or infinite number of HRCs for degenerate Ricci tensor.
Synthesis of chlorophyll-a derivatives possessing various amides as potential sensitizers for photovoltaic cells
Authors: Cui Yuxiao , Ogasawara Shin , Tamiaki Hitoshi
Published: December 2017

3[Formula: see text]-Carboxy-pyropheophorbides-[Formula: see text] possessing a variety of [Formula: see text]-substituted carbamoyl groups at the 17[Formula: see text]-position were prepared by modifying naturally occurring chlorophyll-[Formula: see text]. 3[Formula: see text]-Methoxycarbonyl-pyropheophorbide-[Formula: see text] was obtained via the protection of the 17[Formula: see text]-carboxy group with an allyl group, and amidated with various primary and secondary amines at the free 17-propionate residue, followed by the acidic hydrolysis of the methyl ester in the 3-substituent to give the desired pyropheophorbide-[Formula: see text] secondary and tertiary amides, respectively, bearing the trans-3[Formula: see text]-COOH. The synthetic pigments potentially usable for dye-sensitized solar cells gave almost the same optical properties in a solution.
Fast Water Simulation Methods for Games
Authors: Kellomäki Timo
Published: December 2017

Easy-to-use physics engines have created a whole new source of emergence and fun for digital games. Water simulation could add another similar emergent interaction element in 3D games. Several barriers that prevent this step for games with large playing areas are analysed. One of the most important problems is how to couple the water and physics simulations. Our implementation of the extremely fast virtual pipe method is compared with more sophisticated solvers. Also, two different implementations of physics coupling are compared.
Video Games and Operations Research
Authors: Ripamonti Laura Anna , Trubian Marco , Maggiorini Dario , Previti Simone
Published: December 2017

Despite the effectiveness of Operations Research (OR) in solving complex problems, its use is still somewhat limited due to difficulties experienced by users when describing a real system through a mathematical model. As a result, teaching how to approach and model complex problems is still an open issue. At the same time, it is impossible to deny the strong relation between (video) games and learning. In this paper we are combining the two considerations above and explore to which extent (real time) simulation video games can be used to as an innovative, stimulating, and compelling tool to teach OR techniques.
Cache me if you can
Authors: Loveless Jacob
Published: December 2017

Building a decentralized Web-delivery model.
Determining Application-Specific Peak Power and Energy Requirements for Ultra-Low-Power Processors
Authors: Cherupalli Hari , Duwe Henry , Ye Weidong , Kumar Rakesh , Sartori John
Published: December 2017

Many emerging applications such as the Internet of Things, wearables, implantables, and sensor networks are constrained by power and energy. These applications rely on ultra-low-power processors that have rapidly become the most abundant type of processor manufactured today. In the ultra-low-power embedded systems used by these applications, peak power and energy requirements are the primary factors that determine critical system characteristics, such as size, weight, cost, and lifetime. While the power and energy requirements of these systems tend to be application specific, conventional techniques for rating peak power and energy cannot accurately bound the power and energy requirements of an application running on a processor, leading to overprovisioning that increases system size and weight. In this article, we present an automated technique that performs hardware–software coanalysis of the application and ultra-low-power processor in an embedded system to determine application-specific peak power and energy requirements. Our technique provides more accurate, tighter bounds than conventional techniques for determining peak power and energy requirements. Also, unlike conventional approaches, our technique reports guaranteed bounds on peak power and energy independent of an application’s input set. Tighter bounds on peak power and energy can be exploited to reduce system size, weight, and cost.
The big IDEA and the PD pipeline
Authors: Nelson Mark R.
Published: December 2017

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Former Computer Science Teachers Association executive director Mark R. Nelson discusses his work with the group to overcome core challenges to computer science education.
The new jobs
Authors: Krakovsky Marina
Published: December 2017

As automation takes on more and more tasks, what will human workers do?
Information hiding
Authors: Mazurczyk Wojciech , Wendzel Steffen
Published: December 2017

The practice of hiding ill-gotten data in digital objects is rising among cyber thieves. New initiatives serve to educate, train, and thwart these activities.
Helping students to understand that outward currents depolarize cells.
Authors: Stewart M
Published: December 2017

The physiology of excitable membranes is a fundamental topic in neuroscience and physiology courses at graduate and undergraduate levels. From the building blocks of ionic gradients and membrane channels whose permeability is selective and variable, we build the concepts of resting potential, action potential, and propagation in neurons and muscle fibers. Many students have an intuitive understanding of the movements of ions and the associated changes in membrane potential. For example, potassium ions leaving a cell through potassium-selective channels become unbalanced positive charges on the outside of the cell (and leave unbalanced negative charges on the inside), thus producing a potential across the membrane with the inside negative with respect to the outside. Later, when we discuss the local circuit currents that underlie propagation or the basis for extracellular stimulation, we make the general statement that "outward currents depolarize cells." Students respond with utter disbelief. Two simple additions to a discussion of membranes are suggested that permit the formulation of a consistent set of rules that apply to everything from the resting and action potentials of nerve and muscle through synaptic potentials and stimulation techniques.
Teaching experimental design to biologists.
Authors: Zolman J F
Published: December 2017

The teaching of research design and data analysis to our graduate students has been a persistent problem. A course is described in which students, early in their graduate training, obtain extensive practice in designing experiments and interpreting data. Lecture-discussions on the essentials of biostatistics are given, and then these essentials are repeatedly reviewed by illustrating their applications and misapplications in numerous research design problems. Students critique these designs and prepare similar problems for peer evaluation. In most problems the treatments are confounded by extraneous variables, proper controls may be absent, or data analysis may be incorrect. For each problem, students must decide whether the researchers' conclusions are valid and, if not, must identify a fatal experimental flaw. Students learn that an experiment is a well-conceived plan for data collection, analysis, and interpretation. They enjoy the interactive evaluations of research designs and appreciate the repetitive review of common flaws in different experiments. They also benefit from their practice in scientific writing and in critically evaluating their peers' designs.
HCO3- and H+ secretion in rat ileum in vivo.
Authors: Podesta R B , Mettrick D F
Published: December 2017

Replacing Cl- in the perfusion fluids decreased the luminal pH of rat ileum perfused in vivo. Varying the initial pH in Cl- depletion studies indicated an equilibrium pH near 6.6. Na+ depletion in Cl- deleted fluids partially inhibited luminal acidification. Addition of HCO3- accelerated Na+ absorption and decreased Cl- absorption. Luminal PCO2 was increased using fluids buffered to initial pH 6.6, suggesting secretion of HCO3- rather than OH-. The decreased HCO3- secretion using Cl- depleted fluids was not due to an acclerated rate of H+ secretion. Reaffirmed and expanded in this study is an ileal H+ secretory process that is partially related to Na+ absorption and direct HCO3- secretion that is related to Cl- and Na+ absorption.
Fetal-maternal distribution of ovine alpha-fetoprotein.
Authors: Lai P C , Mears G J , van Petten G R , Hay D M , Lorscheider F L
Published: December 2017

The concentration of ovine alpha-fetoprotein (AFP) was determined in sheep fetal, maternal, and neonatal sera and amniotic fluid by radioimmunoassay. The fetal serum AFP concentration was highest during the first third of pregnancy and continued to decline with fetal and neonatal development. Total fetal synthesis of AFP was highest during the late middle and early latter third of pregnancy. Amniotic fluid AFP concentration was highest during the early middle third of pregnancy. Maternal serum AFP was not elevated above nonpregnant control levels during the first two-thirds of pregnancy, but instead showed a tendency to be elevated only during the last third of pregnancy. The fetal physiological distributions of ovine and human AFP in fetal serum and amniotic fluid appear to be similar, whereas in maternal serum the pattern of AFP levels differs in the two species as a function of gestational age.
Acrosin of mouse spermatozoa.
Authors: Bhattacharyya A K , Goodpasture J C , Zaneveld L J
Published: December 2017

Mouse spermatozoa possess a neutral proteinase, acrosin, that is to a large extent (70-80%) present in the zymogen (proacrosin) form. Acid extraction yields higher amounts of acrosin than detergent extraction. Synthetic inhibitor studies indicate that mouse acrosin has a serine and histidine at its active site and hydrolyzes the peptide bonds of lysine and arginine but of not phenylalanine. An inhibitor of acrosin is associated with mouse spermatozoa, capable of preventing the activity of at least 60% of all available acrosin. Acrosin activity is essential for fertilization because natural and synthetic inhibitors of mouse acrosin prevent the union of the gametes. Also, the relative inhibitory activity of synthetic agents toward acrosin runs approximately parallel to their antifertility activity. The percent of acrosin in the proacrosin form does not change after capacitating mouse spermatozoa in vitro.
Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid.
Authors: Schwartz M W , Sipols A , Kahn S E , Lattemann D F , Taborsky G J , Bergman R N , Woods S C , Porte D
Published: December 2017

To characterize the relationship between insulin levels in plasma and those in cerebrospinal fluid (CSF), we studied the kinetics of both the uptake of insulin into CSF from plasma and the turnover of insulin within the CSF compartment. Sustained physiological levels of euglycemic hyperinsulinemia (plasma insulin approximately 500 pM) did not alter CSF insulin levels within the 1st h, but by 90 min a significant increase was observed (P less than 0.01). During graded hyperinsulinemic clamps (mean plasma insulin approximately 500-15,000 pM), CSF insulin rose in a dose-dependent fashion. This rise was characterized by an initial delay followed by a continuous increase for the next 150 min. We also found that after brief, high-dose intravenous insulin infusions, the t1/2 of CSF insulin was 143 +/- 7 min (means +/- SE; n = 4), similar to that of CSF turnover by bulk flow. To test the specificity of CSF insulin uptake from plasma, we compared this uptake during intravenous insulin infusions with that of proinsulin, a peptide with reduced affinity for the insulin receptor. We observed a significantly lower increment of CSF proinsulin levels over 180 min (13.6 +/- 1.6 pM; means +/- SE; n = 4) compared with that of insulin (22.4 +/- 0.6 pM; n = 4; P less than 0.01), despite plasma proinsulin levels higher than insulin (1,890 +/- 287 vs. 1,283 +/- 192 pM; P less than 0.001). When corrected for the difference in plasma levels, the uptake of insulin was fivefold greater than that of proinsulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Bile acid profiles within the enterohepatic circulation in a diabetic rat model after bariatric surgeries
Authors: Wei Meng , Shao Yi , Liu Qiao-ran , Wu Qun-zheng , Zhang Xiang , Zhong Ming-wei , Liu Shao-zhuang , Zhang Guang-yong , Hu San-yuan
Published: December 2017

Bile acids (BAs), which are synthesized in the liver and cycled in the enterohepatic circulation, have been recognized as signaling molecules by activating their receptors in the intestine and liver. Serum taurine-conjugated BAs have been shown to be elevated after bariatric surgeries although the postoperative BA profiles within the enterohepatic circulation have not been investigated. Clarification of these profiles could help explain the mechanisms by which bariatric surgery leads to BA profile alterations and subsequent metabolic effects. We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham procedures in an obese diabetic rat model induced by high-fat diet and streptozotocin. The weight loss and antidiabetic effects were evaluated postsurgery. BA profiles in the systemic serum and within the enterohepatic circulation were analyzed, together with the expression of related BA transporters and enzymes at week 12 after surgery. Compared with sham, SG induced sustained weight loss, and both DJB and SG significantly improved glucose tolerance and insulin sensitivity with enhanced glucagon-like peptide 1 secretion. Similar to changes in the serum, BAs, especially taurine-conjugated species, were also elevated in the enterohepatic circulation (bile and portal vein) after DJB and SG. In addition, the expression of key BA transporters and conjugational enzymes was elevated postoperatively, whereas the enzymes responsible for BA synthesis were decreased. In conclusion, DJB and SG elevated BA levels in the systemic serum and enterohepatic circulation, especially taurine-conjugated species, which likely indicates increased ileal reabsorption and hepatic conjugation rather than synthesis.

NEW & NOTEWORTHY Bile acids (BAs) have been implicated as potential mediators of the weight-independent effects of bariatric surgery. For the first time, we discovered that duodenal-jejunal bypass and sleeve gastrectomy elevated BAs, particularly the taurine-conjugated species in the enterohepatic circulation, likely through the promotion of ileal reabsorption and hepatic conjugation rather than BA synthesis. These findings will improve our understanding of BA metabolism after bariatric surgery and their subsequent metabolic effects.
Telomerase reverse transcriptase protects against angiotensin II-induced microvascular endothelial dysfunction
Authors: Ait-Aissa Karima , Kadlec Andrew O. , Hockenberry Joseph , Gutterman David D. , Beyer Andreas M.
Published: December 2017

A rise in reactive oxygen species (ROS) may contribute to cardiovascular disease by reducing nitric oxide (NO) levels, leading to loss of NO’s vasodilator and anti-inflammatory effects. Although primarily studied in larger conduit arteries, excess ROS release and a corresponding loss of NO also occur in smaller resistance arteries of the microcirculation, but the underlying mechanisms and therapeutic targets have not been fully characterized. We examined whether either of the two subunits of telomerase, telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC), affect microvascular ROS production and peak vasodilation at baseline and in response to in vivo administration to angiotensin II (ANG II). We report that genetic loss of TERT [maximal dilation: 52.0 ± 6.1% with vehicle, 60.4 ± 12.9% with Nω-nitro-l-arginine methyl ester (l-NAME), and 32.2 ± 12.2% with polyethylene glycol-catalase (PEG-Cat) ( P < 0.05), means ± SD, n = 9–19] but not TERC [maximal dilation: 79 ± 5% with vehicle, 10.7 ± 9.8% with l-NAME ( P < 0.05), and 86.4 ± 8.4% with PEG-Cat, n = 4–7] promotes flow-induced ROS formation. Moreover, TERT knockout exacerbates the microvascular dysfunction resulting from in vivo ANG II treatment, whereas TERT overexpression is protective [maximal dilation: 88.22 ± 4.6% with vehicle vs. 74.0 ± 7.3% with ANG II (1,000 ng·kg−1·min−1) ( P = not significant), n = 4]. Therefore, loss of TERT but not TERC may be a key contributor to the elevated microvascular ROS levels and reduced peak dilation observed in several cardiovascular disease pathologies.

NEW & NOTEWORTHY This study identifies telomerase reverse transcriptase (TERT) but not telomerase RNA component as a key factor regulating endothelium-dependent dilation in the microcirculation. Loss of TERT activity leads to microvascular dysfunction but not conduit vessel dysfunction in first-generation mice. In contrast, TERT is protective in the microcirculation in the presence of prolonged vascular stress. Understanding the mechanism of how TERT protects against vascular stress represents a novel target for the treatment of vascular disorders.
Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment
Authors: Van Skike Candice E. , Jahrling Jordan B. , Olson Angela B. , Sayre Naomi L. , Hussong Stacy A. , Ungvari Zoltan , Lechleiter James D. , Galvan Veronica
Published: December 2017

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer’s disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR−/−) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR−/− mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity.

NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.
Fluid volumes during onset of spontaneous hypertension in rats
Authors: Trippodo N. C. , Walsh G. M. , Frohlich E. D.
Published: December 2017

Body fluid volumes were examined in young spontaneously hypertensive rats (SHR) and in two strains of age-matched normotensive controls to ascertain whether expanded plasma volume (PV) or extracellular fluid volume (ECFV) was associated with onset of spontaneous hypertension. Mean arterial pressure (MAP) was measured in conscious male SHR, Wistar-Kyoto normotensive (WKY), and American Wistar normotensive (NR) rats 3 h after arterial cannulation. At age 10-14 days no differences in MAP or PV (determine with 125I-albumin) were found between SHR and WKY. At age 18-43 days, SHR had elevated MAP and a small but significant elevation in total body water volume (TBWV; wet weight minus dry weight) compared to WKY and NR; no differences among the three groups were found in PV or ECFV (estimated with inulin). These results provide no evidence that expanded PV or ECFV plays a role in the pathogenic mechanisms of spontaneous hypertension, but do not exclude the possibility of altered vascular compliance. The slightly elevated TBWV in SHR may be related to reduced body fat in SHR.
Intestinal mucosal oxygenation influences absorptive hyperemia
Authors: Bohlen H. Glenn
Published: December 2017

Intestinal villus oxygen tension (PO2) is decreased from normal values of 14-17 to 4-7 mmHg, and blood flow is nearly doubled during glucose absorption. The current study evaluated The role of oxygen supply to the mucosa in the absorptive hyperemia mechanism. With a constant PO2 (40-45 mmHg) over the intestinal muscle layer, the mucosal tissue PO2 increased only 4-5 mmHg, and intestinal blood flow decreased from about 125 to 65% of control (PO2 = 4045) as the mucosal solution PO2 increased from 5 to 75 mmHg. When glucose was present (100 mg/100 mL), mucosal tissue PO2 was s-7 mmHg at mucosal suffusion PO2 of s-75 mmHg. When glucose was present (100 mg/100 mL), mucosal tissue PO2 was s-7 mmHg at mucosal suffusion PO2 of s-75 mmHg. Blood flow in the presence of glucose was 210 and 110% of control at a solution PO2 of 5-10 and 70-75 mmHg. Tissue PO2 in the vicinity of the submucosal series arterioles was only slightly affected by all of the manipulations described. At rest or during glucose exposure, elevation of mucosal solution PO2 caused constriction, and lowering the mucosal solution PO2 caused dilation even though tissue PO2 in the various regions of the bowel wall remained nearly constant. The data indicate that the supply of oxygen available for the tissue rather than the actual tissue PO2 is best correlated to oxygen's role in control of arterioles throughout the intestine during absorptive hyperemia.
Contractile function in chronic gradually developing subcoronary aortic stenosis
Authors: Carabello B. A. , Mee R. , Collins J. J. , Kloner R. A. , Levin D. , Grossman W.
Published: December 2017

Whether hypertrophied cardiac muscle functions normally or abnormally is a point of controversy in the literature. Most animal studies showing depressed performance of hypertrophied cardiac muscle have used experimental methods in which hypertrophy was produced by acutely imposing a pressure overload on the left or right ventricle, which may cause myocardial injury. To assess the possibility that chronic, slowly developing hypertrophy is associated with normal myocardial function, we developed an experimental model in which increased afterload is imposed gradually on the left ventricle in the dog. A snug band was placed around the aorta beneath the left coronary artery in puppies without producing a stenosis. As the puppies grew, relative aortic stenosis developed as increased cardiac output flowed across that fixed outflow area. One group (group A) of six puppies was banded early, whereas a second group (group B, five puppies) was banded late and served as controls. Left ventricular weight (g) to body weight (kg) ratio remained normal in group B animals (3.9 +/- 0.14), whereas this ratio was increased to 5.3 +/- 0.24 (P < 0.001) in group A animals indicating development of moderate cardiac hypertrophy. Ejection fraction, dP/dt, Vcf, and stroke work per gram of myocardium were virtually identical in both groups. We conclude that moderate, gradually developing cardiac hypertrophy as produced by this model is associated with normal myocardial contractile performance.
Cardiac output during cardiopulmonary resuscitation at various compression rates and durations
Authors: Fitzgerald K. R. , Babbs C. F. , Frissora H. A. , Davis R. W. , Silver D. I.
Published: December 2017

Cardiac output during cardiopulmonary resuscitation (CPR) was measured by a modified indicator-dilution technique in 20 anesthetized dogs (6-12 kg), during repeated 1- to 2-min episodes of electrically induced ventricular fibrillation, by a mechanical chest compressor and ventilator. With compression rates from 20 to 140/min and compression durations (duty cycles) from 10 to 90% of cycle time, cardiac output (CO) was predicted by the equation: CO = CR . SVmax . [DC/(k1 . CR + DC)] . [(1 — DC)/k2 . CR + 1 - DC)], where CR is compression rate, DC is duty cycle, SVmax (19 ml) is the effective capacity of the pumping chamber, and k1 (0.00207 min) and k2 (0.00707 min) are ejection and filling constants. This expression predicts maximal CO for DC = 0.40 and cR = 126/min and 90-100% of maximal CO for 0.3 less than DC less than 0.5 and 70 less than CR less than 150/min. Such mathematical analysis may prove useful in the optimization of CPR.
Human sinus node responses to repetitive, ramped carotid baroreceptor stimuli
Authors: Eckberg D. L. , Eckberg M. J.
Published: December 2017

When arterial pressure rises spontaneously, baroreceptor areas are presented with repetitive stimuli of progressively increasing intensities. We simulated rising arterial pressure in 18 healthy young adults by applying trains of repetitive, ramped, R-wave-coupled neck suction, and we related P-P interval responses to intensities of stimuli with least-squares linear regression. We found that the P-P interval response to the stimulus train we used is immediate and highly linear (most correlation coefficients were above 0.90). In studies in which the base-line heart rate was less than 75 beats/min, cardiac inhibition was maximal in the cardiac cycle in which the stimulus was delivered. Decay of inhibition commences rapidly after the end of baroreceptor stimulation and proceeds with time constants that are independent of maximum levels of inhibition. P-P interval shortening (cardioacceleration) comprises an integral feature of baroreflex responses, such that inhibitory stimuli set in motion oscillations of heart period above and below base-line levels. Our data suggest that the pattern of sinus node responses during transitions of arterial pressure results from a complex interplay among several factors, including baroreflex responsiveness, base-line heart rate, the rate decay of baroreflex inhibition, and the biphasic nature of sinus node responses to inhibitory cholinergic interventions.
Phosphorus nuclear magnetic resonance spectroscopy of cardiac and skeletal muscles
Authors: Ingwall J. S.
Published: December 2017

Phosphorus nuclear magnetic resonance spectroscopy (P-31 NMR) has been used to assess dynamic aspects of the metabolism of phosphorus-containing compounds in intact cells, organs, and animals. This review describes the NMR experiment and the kinds of information the P-31 NMR spectrum provides for intact, functioning cardiac and skeletal muscles. The P-31 NMR spectrum not only identifies which phosphorus-containing compounds are present in high concentration, namely adenosine 5'-triphosphate (ATP) and creatine phosphate, but also provides information about their chemical environment (including pH) and intracellular distribution. The method is quantitative and nondestructive and permits repetitive measurements in an intact functioning organ. For the perfused heart, it is possible to manipulate the chemical and gaseous composition of the perfusate and to define the effects of, for example, ischemia and reperfusion on the metabolism of ATP and creatine phosphate in the same sample. Using saturation-transfer NMR techniques, it is also possible to measure rates of certain reactions, including creatine kinase and adenylate kinase, in the intact cell. NMR can also be used as an imaging modality.
Fluid dynamics of the mitral valve: physiological aspects of a mathematical model
Authors: McQueen D. M. , Peskin C. S. , Yellin E. L.
Published: December 2017

This paper presents a computational method that can be used to study the fluid computational method that can be used to study the fluid dynamics of the natural or prosthetic mitral valve in a computer test chamber with contractile muscular walls that model the left side of the heart. Having solved the equations of motion and predicted the performance of the valve, the computer presents the results in terms of flow patterns (streamlines), pressure-contour plots, and graphs of velocity, pressure, flow, tension, and distance as functions of time. Predicted echocardiograms and phonocardiograms are also generated by the computer. These predictions are compared with the results of animal experiments, and the method is used to study the diastolic role of the chordae tendineae, the pathophysiology of mitral valve prolapse syndrome, and the fluid dynamics of pivoting disc valves. Our results support the hypothesis that the chordae have a functional role during diastole. The results also establish a computer model of mitral prolapse, which should be useful in functional studies of that condition, and show that the position of the pivot point and the curvature of the occluder can have a profound effect on the angle of opening of pivoting disc valves. These studies illustrate the applications of the method in physiology, pathophysiology, and prosthetic valve design.
Morphometry of right ventricular hypertrophy induced by strenuous exercise in rat
Authors: Anversa P. , Beghi C. , Levicky V. , McDonald S. L. , Kikkawa Y.
Published: December 2017

Effects on the myocardium, particularly those structural properties of the capillary network relevant to tissue oxygenation, were studied morphometrically in rats subjected to a severe running program. Physical conditioning produced a 31% increase in right ventricular weight and only a 12% increase in the weight of the left ventricle. Quantitative analysis of right ventricular myocardium demonstrated relative decreases in capillary luminal volume density (-27%) and capillary luminal surface density (-20%) and an increase in the average maximum distance from the capillary wall to the mitochondria of myocytes (14%). In contrast, the contractile mass expanded in proportion to the growth of the ventricle through augmentation of the cross-sectional area (17%) and length (19%) of the average myocyte. Evaluation of the subcellular constituents of myocytes showed no change in the mitochondria-to-myofibril volume ratio. In conclusion, the capillary bed controlling oxygen availability, diffusion, and transport suggests that excessive physical activity may be detrimental to the myocardium.
Isolated atrial myocytes: adenosine and acetylcholine increase potassium conductance
Authors: Belardinelli L. , Isenberg G.
Published: December 2017

Adenosine (Ado), like acetylcholine (ACh), hyperpolarizes and shortens the atrial action potential (AP). To elucidate the underlying mechanism of Ado and ACh actions, intracellular APs and membrane currents were measured in calcium-tolerant single myocytes isolated from guinea pig atria. Both Ado and ACh hyperpolarize the resting membrane to the potassium equilibrium potential (Ek) and cause a marked abbreviation of the AP. Analysis of membrane currents reveal that Ado and ACh increase the steady-state currents. The Ado- and ACh-induced current reverses polarity at -92 mV, a value that corresponds well with a calculated EK of -90 mV. Thus the Ado- and the ACh-sensitive current can be interpreted as a potassium current. It is suggested that Ado, like ACh, increases the potassium conductance via a common mechanism.
Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis
Authors: Rouslin W.
Published: December 2017

Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. The activities of the five mitochondrial inner membrane enzyme complexes of electron transport and coupled oxidative phosphorylation were assayed as a function of time of ischemia or autolysis. While the activities of complex II (succinate-CoQ reductase) and IV (cytochrome c oxidase) were completely stable, that of complex I (NADH-CoQ reductase) decreased markedly, but largely only after 20 min of ischemia or autolysis. At 20 min and beyond, the decrease in the activity of complex I paralleled closely the decrease in whole mitochondrial oxygen uptake with NAD-linked substrates in both models. The activity of complex III (CoQH2-c reductase) decreased at a more gradual rate during ischemia or autolysis, and its rate of decrease paralleled that of succinate-supported oxygen uptake. The activity of complex V (oligomycin-sensitive ATPase) decreased most rapidly (by 40% in only 5 min of autolysis) but nearly leveled off beyond 20 min in the two models. A strikingly similar pattern of differential enzyme lability was observed in isolated control mitochondria incubated at lowered pH values. The results demonstrate 1) differential enzyme lability within the mitochondrial inner membrane, 2) a connection between severity of acidosis and the degree of enzyme activity loss, and 3) the usefulness of simple tissue autolysis as an analogue of in situ myocardial ischemia.
Cycle length effect on restitution of action potential duration in dog cardiac fibers
Authors: Elharrar V. , Surawicz B.
Published: December 2017

Electrical restitution of action potential duration (APD) was determined in Purkinje (n = 8) and ventricular muscle (n = 6) fibers at two different basic cycle lengths (BCL, 1,500 and 500 ms). Restitution curves, normalized for the longest APD (the plateau of restitution), fitted the sum of a fast (T1) and a slow (T2) exponential component. The T1 was shorter in ventricular muscle than Purkinje fibers (89 +/- 5 and 143 +/- 9; mean +/- SE, P less than 0.05), whereas the T2 did not differ (1,448 +/- 231 and 1,439 +/- 211). The BCL altered the APD value during the plateau of restitution but did not change the two exponential components. In both fiber types, the relation between APD and BCL during steady state fitted a hyperbolic curve that predicts the achievement of the maximum APD at long BCL. The restitution curves crossed the steady-state curve at two points outlining three different zones of APD intervals: early premature, late premature, and postmature. The APD during restitution was longer than the steady state in the late premature zone and shorter than the steady-state APD in the post-mature and early premature zones. The APD per se, independent of BCL, did not influence the kinetics of restitution in Purkinje fibers.