bluuebunny/crossref_metadata_2025 huggingface dataset:
Attitudes to morphine in chronic heart failure patients
Authors: Oxberry Stephen G , Jones Lesley , Clark Andrew L , Johnson Miriam J
Published: August 2012

Objectives

Low-dose opioids are used for the palliation of pain, breathlessness and cough in advanced chronic heart failure (CHF) patients. The authors wanted to determine any potential barriers or facilitators to opioid administration in patients with CHF by assessing their knowledge, concerns and attitudes to morphine therapy.

Methods

Semistructured interviews were held with a purposive sample of 10 men with symptoms of CHF. Data were analysed using a constant comparative approach until thematic saturation.

Results

Four key areas emerged: medication use; symptoms; prior morphine experience; and attitudes, concerns and anxieties regarding morphine use. Despite polypharmacy, participants said that morphine would be acceptable if it was monitored by a trusted healthcare professional. Many patients had experienced morphine before, often in life-threatening situations such as myocardial infarction, when it had helped greatly. Opioids were not strongly associated exclusively with death and dying (in contrast to patient reports in the cancer literature).

Conclusions

Although some concerns about morphine were expressed, these did not appear to override a willingness to consider its use if recommended by a trusted clinician. However, some participants perceived that their doctor was concerned about its use, holding it as a last reserve. Morphine appears to be an acceptable breathlessness treatment option to these people with CHF. Prescribers may need education and reassurance if these medicines are to be used to their full potential and views may be different in other communities.
Republished: Development and evaluation of a 3-day patient safety curriculum to advance knowledge, self-efficacy and system thinking among medical students
Authors: Aboumatar Hanan J , Thompson David , Wu Albert , Dawson Patty , Colbert Jorie , Marsteller Jill , Kent Paula , Lubomski Lisa H , Paine Lori , Pronovost Peter
Published: August 2012

Purpose

To develop a patient safety curriculum and evaluate its impact on medical students' safety knowledge, self-efficacy and system thinking.

Methods

This study reports on curriculum development and evaluation of a 3-day, clinically oriented patient safety intersession that was implemented at the Johns Hopkins School of Medicine in January 2011. Using simulation, skills demonstrations, small group exercises and case studies, this intersession focuses on improving students' teamwork and communication skills and system-based thinking while teaching on the causes of preventable harm and evidence-based strategies for harm prevention. One hundred and twenty students participated in this intersession as part of their required second year curriculum. A pre–post assessment of students' safety knowledge, self-efficacy in safety skills and system-based thinking was conducted. Student satisfaction data were also collected.

Results

Students' safety knowledge scores significantly improved (mean +19% points; 95% CI 17.0 to 21.6; p<0.01). Composite system thinking scores increased from a mean pre-intersession score of 60.1 to a post-intersession score of 67.6 (p<0.01). Students had statistically significant increases in self-efficacy for all taught communication and safety skills. Participant satisfaction with the intersession was high.

Conclusions

The patient safety intersession resulted in increased knowledge, system-based thinking, and self-efficacy scores among students. Similar intersessions can be implemented at medical, nursing, pharmacy and other allied health schools separately or jointly as part of required school curricula. Further study of the long-term impact of such education on knowledge, skills, attitudes and behaviours of students is warranted.
Falling mortality rates in Type 2 diabetes mellitus in the Wirral Peninsula: a longitudinal and retrospective cohort population-based study
Authors: Nwaneri Chukwuemeka , Bowen-Jones David , Cooper Helen , Chikkaveerappa Krishnamurthy , Afolabi Banjo Adekunle
Published: August 2012

Objectives

To determine the life expectancy and mortality rates in patients with type 2 diabetes mellitus when compared with the UK general population; to measure the years of life lost.

Design

Longitudinal and retrospective cohort study.

Setting

The Wirral Peninsula in the northwest of England.

Participants

Total of 13 620 patients with type 2 diabetes mellitus on the Wirral Diabetes Register.

Main Outcome measure

All-cause mortality, from 1 January 2000 to 31 December 2007.

Results

Over the 8-year period of the study, there were a total of 16 692.5 person-years lived and 3888 deaths; 2041 (52.5%) males and 1847 (47.5%) females with corresponding mean ages at death of 75.6±10.3 years and 80.2±10.2 years, respectively. Although prevalence rates increased linearly (from 1.06% in 2000 to 4.39% in 2007) a decrease in mortality rates (from 117 to 46 per 1000 population) in both sexes was observed. This coincided with a progressive fall in cardiovascular risk factors in this population. A survival time curve of life lived until death showed that males had 8.0 years reduction in life span and females' life span was reduced by 9.6 years when compared with UK general population. In both sexes, life expectancy was reduced by between 2 and 11 years dependent on the age of diagnosis, with males showing a greater degree of reduction.

Conclusion

Type 2 diabetes mellitus is associated with a significant reduction in life expectancy, more markedly in men, and in those diagnosed before age 70 years. However, annual mortality rates have fallen progressively in our population and may contribute to longer survival and life expectancy in future years.
Chromosomal characterization in native populations of Elymus scabrifolius from Argentina through classical and molecular cytogenetics (FISH–GISH)
Authors: Tomas P.A. , González G.E. , Schrauf G.E. , Poggio L.
Published: August 2012

The karyotype of Elymus scabrifolius (Döll) J.H. Hunz. (2n = 4x = 28) was investigated by DAPI staining and in situ hybridization. All the accessions studied presented a symmetric and uniform karyotype constituted by 9m+2m–sm+3sm. DAPI stain showed 1–7 conspicuous bands in all the chromosomes and polymorphisms between accessions. FISH experiments carried out with 45S rDNA as probe (pTa71) showed strong hybridization signals on the metacentric SAT-chromosome pair 8; the submetacentric SAT-chromosome pair 13 presented weaker hybridization. FISH using pSc119.2 clone as probe identified five chromosome pairs. Then, the combination of chromosome morphology, DAPI-staining, and FISH enabled the accurate identification of each chromosome pair in E. scabrifolius. Genomic in situ hybridization (GISH) experiments using Hordeum DNA as probe on mitotic metaphases confirmed unequivocally the presence of the H genome in E. scabrifolius, allowing us to observe six uniformly labeled chromosome pairs and two chromosome pairs with only one arm labeled. The remaining six chromosome pairs were weakly labeled. The rehybridization of FISH slides with Hordeum DNA as probe allow us to assign the genomic provenance of most of the chromosomes in the studied accessions. Moreover, intergenomic rearrangement was detected between genome H and the still unknown progenitor genome.
ON SUPERCYCLIC OPERATORS WITH ADJOINTS HAVING NONEMPTY POINT SPECTRUM
Authors: FAGHIH-AHMADI M.
Published: August 2012

Let T be a bounded linear operator on an infinite dimensional, separable Banach space X. We consider a class of supercyclic operators, whose point spectrum of their adjoints are nonempty, and prove that under certain conditions, the orbit of every supercyclic vector for such an operator is unbounded. This result has some nice applications: (1) We obtain some conditions equivalent to the supercyclicity of extreme points of the closed unit ball of [Formula: see text] on a separable infinite dimensional Hilbert space; this helps us to characterize all supercyclic operators in this class. (2) The adjoint of composition operators on certain weighted Hardy spaces are never supercyclic. Next, we turn our attention to the commutant and show that if T is an operator in the mentioned class, then every operator in the commutant of T is not hypercyclic.
A TOY MODEL TO STUDY THE PEAK OF CHIRAL SUSCEPTIBILITY AND CHIRAL PHASE TRANSITION AT FINITE TEMPERATURE
Authors: ZHOU YU-QING , KE DONG , FENG HONG-TAO
Published: August 2012

In this paper, the chiral susceptibility and fermion chiral condensate are investigated in the same framework for Dyson–Schwinger equation. We show that, with the rise of temperature, the susceptibility gives a sharp peak where the chiral symmetry restores. The appearance of the peak and restoration at the same temperature suggests that the peak of chiral susceptibility can be treated as the hint for the restoration of chiral phase transition with the increasing temperature.
COLOR CORRECTION FOR HIGH-DEFINITION ELECTRONIC ENDOSCOPE
Authors: CHEN JING , WANG LI-QIANG , MENG ZI-BO , YUAN BO , DUAN HUI-LONG
Published: August 2012

The subtle color distinction is the important function of electronic endoscope imaging diagnosis. However, after image acquisition, transmission and display, color distortions of intracorporeal organs or tissues occur inevitably, which are adverse to analyze image features accurately or to diagnose early pathological changes. A real-time color correction algorithm based on four-neighborhood and polynomial regression in YUV color space is proposed. Based on polynomial regression the color correction matrix is calculated in YUV color space according to the differences between standard values of color checker and measured values of that imaged by the endoscope. As the correction is only executed on U and V components in YUV color space, the defect that the color of corrected images in RGB color space will change along with luminance can be avoided, and then the stability of image color is improved. Owing to four-neighborhood processing, the signal-to-noise ratio of corrected images is enhanced and the processing speed of correction algorithm is accelerated. The average color difference is reduced from 0.3944 to 0.2850 by application of the proposed algorithm in high-definition electronic endoscope. A total of 17 frames per second can be achieved at the resolution of 1280 × 800, and the color characteristics of the image after processing match that of human visual system.
Magnetostratigraphy, fence diagrams and basin analysis
Authors: Yan Maodu , Van Der Voo Rob , Fang Xiao-Min , Song Chunhui
Published: August 2012

Correlation of lithostratigraphic sections is widely used to examine the nature of lateral facies changes within or between basins. It can provide significant clues for regional environmental and palaeogeographic reconstructions. There are problems associated with lithostratigraphic correlation; diachronous deposition of similar lithological units may not be recognized. We report here an attempt to determine lateral facies changes in coeval sedimentary sections, through three-dimensional magnetostratigraphic correlations in the Guide Basin, an intramontane basin in the northeastern part of the Tibetan Plateau. The method is successful for correlating lateral facies and helps to identify sediment sources in the basin.
Oligocene–Miocene magnetostratigraphy of deep-sea sediments from the equatorial Pacific (IODP Site U1333)
Authors: Guidry E. P. , Richter C. , Acton G. D. , Channell J. E. T. , Evans H. F. , Ohneiser C. , Yamamoto Y. , Yamazaki T.
Published: August 2012

We present palaeomagnetic results from the Oligocene through Miocene part of the Integrated Ocean Drilling Program Site U1333 (1030.996′N, 138°25.159′W), which is located in 4853 m-deep water over seafloor with an estimated crustal age of 46 Ma. Detailed magnetostratigraphic investigations are essential to provide a sound age model for the study of the palaeoclimatic and palaeo-oceanographic history of the Cenozoic of the Equatorial Pacific and to improve the database of Pacific magnetostratigraphy. Rock magnetic measurements were carried out at 1 cm resolution on 81 U-channel samples from the spliced section with the goal of extracting a high-resolution record of the magnetostratigraphy. Stepwise demagnetization of the natural remanent magnetization yielded a well-defined magnetostratigraphy over a time interval of approximately 10 Ma between the base of Chron C6n (19.722 Ma) and the middle of Chron C11r (>29.9 Ma) and identification of the Oligocene–Miocene transition at the base of Subchron C6Cn.2n. The palaeomagnetic data are characterized by shallow inclinations, and by 180° alternations in declinations downhole, reflecting magnetic polarity zones. The relatively high temporal resolution allowed for the identification of three possible excursions previously not identified on the geomagnetic polarity time scale, which were recorded in Subchrons C8n.1r and C11n.2n and in Chron C11r.
α-Crystallin B prevents apoptosis after H2O2 exposure in mouse neonatal cardiomyocytes
Authors: Chis Roxana , Sharma Parveen , Bousette Nicolas , Miyake Tetsuaki , Wilson Aaron , Backx Peter H. , Gramolini Anthony O.
Published: August 2012

α-Crystallin B (cryAB) is the most abundant small heat shock protein in cardiomyocytes (CMs) and has been shown to have potent antiapoptotic properties. Because the mechanism by which cryAB prevents apoptosis has not been fully characterized, we examined its protective effects at the cellular level by silencing cryAB in mouse neonatal CMs using lentivector-mediated transduction of short hairpin RNAs. Subcellular fractionation of whole hearts showed that cryAB is cytosolic under control conditions, and after H2O2 exposure, it translocates to the mitochondria. Phosphorylated cryAB (PcryAB) is mainly associated with the mitochondria, and any residual cytosolic PcryAB translocates to the mitochondria after H2O2 exposure. H2O2 exposure caused increases in cryAB and PcryAB levels, and cryAB silencing resulted in increased levels of apoptosis after exposure to H2O2. Coimmunoprecipitation assays revealed an apparent interaction of both cryAB and PcryAB with mitochondrial voltage-dependent anion channels (VDAC), translocase of outer mitochondrial membranes 20 kDa (TOM 20), caspase 3, and caspase 12 in mouse cardiac tissue. Our results are consistent with the conclusion that the cardioprotective effects of cryAB are mediated by its translocation from the cytosol to the mitochondria under conditions of oxidative stress and that cryAB interactions with VDAC, TOM 20, caspase 3, and caspase 12 may be part of its protective mechanism.
The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms
Authors: Remus Ebony Washington , O'Donnell Robert E. , Rafferty Kathryn , Weiss Daiana , Joseph Giji , Csiszar Katalin , Fong Sheri F. T. , Taylor W. Robert
Published: August 2012

Abdominal aortic aneurysms (AAAs) are a major cause of morbidity and mortality in the United States today. We employed a model for AAA development using apolipoprotein E knock out mice fed a high-fat diet and treated with ANG II and β-aminopropionitrile (β-APN) for 4 wk. ANG II induces hypertension and atherosclerotic disease, whereas β-APN inhibits the activity of the lysyl oxidase/ lysyl oxidase-like protein (LOX/LOXL) family members. LOX/LOXL family members crosslink collagen and elastin in the extracellular matrix and therefore contribute to the integrity and stabilization of a healthy vessel wall. In this model, cotreatment with ANG II and β-APN caused a 90% AAA incidence and increased atherosclerotic lesion formation from less than 5% to greater than 25% after 4 wk. In more atheroprotected mouse strains (C57BL/6 and BalbC), cotreatment with ANG II and β-APN caused 50% and 40% AAA incidence, respectively. These data demonstrate the importance of LOX/LOXL to the stability of the vessel wall. Therapeutic strategies to overexpress LOX/LOXL enzymes or to support the crosslinking of soluble matrix proteins in a polymeric scaffold are a promising opportunity to achieve stabilization of AAAs.
A time course investigation of the statin paradox among valvular interstitial cell phenotypes
Authors: Monzack Elyssa L. , Masters Kristyn S.
Published: August 2012

Statin drugs are prescribed primarily for their ability to lower cholesterol, but may also exert beneficial side effects unrelated to cholesterol metabolism. Previous work has described a “statin paradox,” where statin treatment decreased osteoblastic markers in valve myofibroblasts while increasing those same markers in preosteoblasts. However, valvular interstitial cells (VICs) themselves are a multipotent cell type, capable of differentiating into activated, myofibroblastic VICs (aVICs) and osteoblastic VICs (obVICs), motivating the question of whether the statin paradox can exist within an individual valve containing these phenotypically distinct VIC subpopulations. In the current study, a heterogeneous initial population of porcine VICs was differentiated into aVICs or obVICs and treated with simvastatin. Gene expression analysis was conducted daily over an 8-day time course to capture temporally dynamic changes in cell phenotype induced by statin treatment. These studies demonstrated that the two VIC populations, aVICs and obVICs, exhibited differential responses to statin treatment. Specifically, simvastatin increased the expression of osteoblastic markers in obVICs, but not in aVICs, while also suppressing the myofibroblastic phenotype in both aVICs and obVICs. These results indicate that the statin paradox can exist within the heterogeneous VIC population of an individual diseased valve and that statin efficacy in the context of calcific aortic valve disease (CAVD) may be dependent upon the cellular composition of the valve. These findings may have implications for clinical usage of statins, shedding light on how statin efficacy in CAVD may be dependent upon the disease stage or why some individuals exhibit better responsiveness to statin therapy.
Regulation of cardiac alternans by β-adrenergic signaling pathways
Authors: Florea Stela M. , Blatter Lothar A.
Published: August 2012

In cat atrial myocytes, β-adrenergic receptor (β-AR) stimulation exerts profound effects on excitation-contraction coupling and cellular Ca2+cycling that are mediated by β1- and β2-AR subtypes coupled to G proteins (Gsand Gi). In this study, we determined the effects of β-AR stimulation on pacing-induced Ca2+alternans. Ca2+alternans was recorded from single cat atrial myocytes with the fluorescent Ca2+indicator indo-1. Stable Ca2+alternans occurred at an average pacing frequency of 1.7 Hz at room temperature with a mean alternans ratio of 0.43. Nonselective β-AR stimulation as well as selective stimulation of β1/Gs, β2/Gs+ Gi, and β2/Gscoupled pathways all abolished pacing-induced Ca2+alternans. β1-AR stimulation abolished alternans through stimulation of PKA and Ca2+/calmodulin-dependent protein kinase II, whereas β2-AR stimulation exclusively involved PKA and was mediated via Gs, whereas a known second pathway in cat atrial myocytes acting through Giand nitric oxide production was not involved in alternans regulation. Inhibition of various mitochondrial functions (dissipation of the mitochondrial membrane potential or inhibition of mitochondrial F1/F0-ATP synthase, mitochondrial Ca2+uptake via the mitochondrial Ca2+uniporter, and Ca2+extrusion via mitochondrial Na+/Ca2+exchange) enhanced Ca2+alternans; however, β-AR stimulation still abrogated alternans, provided that sufficient cellular ATP was available. Selective inhibition of mitochondrial or glycolytic ATP production did not prevent β-AR stimulation from abolishing Ca2+alternans. However, when both ATP sources were depleted, β-AR stimulation failed to decrease Ca2+alternans. These results indicate that in atrial myocytes, β-AR stimulation protects against pacing-induced alternans by acting through parallel and complementary signaling pathways.
Effect of global and regional sympathetic blockade on arterial pressure during water deprivation in conscious rats
Authors: Veitenheimer Britta J. , Engeland William C. , Guzman Pilar A. , Fink Gregory D. , Osborn John W.
Published: August 2012

Forty-eight hours of water deprivation (WD) in conscious rats results in a paradoxical increase in mean arterial pressure (MAP). Previous studies suggest this may be due to increased sympathetic nerve activity (SNA). However, this remains to be investigated in conscious, freely behaving animals. The purpose of this study was to determine, in conscious rats, the role of the sympathetic nervous system (SNS) in mediating WD-induced increases in MAP and to identify which vascular beds are targeted by increased SNA. Each rat was chronically instrumented with a radiotelemetry transmitter to measure MAP and heart rate (HR) and an indwelling venous catheter for plasma sampling and/or drug delivery. MAP and HR were continuously measured during a 2-day baseline period followed by 48 h of WD and then a recovery period. By the end of the WD period, MAP increased by ∼15 mmHg in control groups, whereas HR did not change significantly. Chronic blockade of α1/β1-adrenergic receptors significantly attenuated the WD-induced increase in MAP, suggesting a role for global activation of the SNS. However, the MAP response to WD was unaffected by selective denervations of the hindlimb, renal, or splanchnic vascular beds, or by adrenal demedullation. In contrast, complete adrenalectomy (with corticosterone and aldosterone replaced) significantly attenuated the MAP response to WD in the same time frame as α1/β1-adrenergic receptor blockade. These results suggest that, in conscious water-deprived rats, the SNS contributes to the MAP response and may be linked to release of adrenocortical hormones. Finally, this sympathetically mediated response is not dependent on increased SNA to one specific vascular bed.
Constitutively active MEK1 rescues cardiac dysfunction caused by overexpressed GSK-3α during aging and hemodynamic pressure overload
Authors: Maejima Yasuhiro , Galeotti Jonathan , Molkentin Jeffery D. , Sadoshima Junichi , Zhai Peiyong
Published: August 2012

Expression of GSK-3α is increased in aging hearts and those subjected to hemodynamic overload. Overexpressed GSK-3α inhibits ERK and enhances pressure overload (PO)-induced cardiac dysfunction. We studied whether suppression of the MEK1/ERK pathway contributes to cardiac responses induced by overexpressed GSK-3α using constitutively active MEK1 (CA-MEK1)/GSK-3α bigenic mice (bigenic mice), which were obtained by crossing cardiac-specific GSK-3α transgenic mice (Tg-GSK) and cardiac-specific CA-MEK1 transgenic mice (Tg-MEK1). The suppression of ERK phosphorylation observed in Tg-GSK was eliminated in bigenic mice. At 12 mo, left ventricular (LV) weight/tibia length, LV weight/body weight, and cardiac myocyte size were significantly smaller in Tg-GSK than in nontransgenic mice (NTg), but were not significantly different between Tg-MEK1 and bigenic mice. The LV ejection fraction (LVEF), fractional shortening (FS), and change in pressure over time were significantly lower in Tg-GSK than in NTg, but were not significantly different between bigenic mice and Tg-MEK1. The increase in apoptosis in Tg-GSK was abolished in bigenic mice, although the increase in fibrosis was not. After PO, the decrease in cardiac hypertrophy and the enhancement of apoptosis seen in Tg-GSK were abrogated in bigenic mice. After PO, the LVEF and FS were significantly reduced in Tg-GSK compared with its sham, but not in NTg, Tg-MEK1, or bigenic mice compared with their respective shams. There was no significant difference in LVEF and FS between bigenic mice and Tg-MEK1 after PO. In conclusion, inhibition of the MEK1/ERK pathway mediates the hypertrophy suppression and cardiac dysfunction caused by GSK-3α overexpression in cardiac myocytes.
The history of matrix metalloproteinases: milestones, myths, and misperceptions
Authors: Iyer Rugmani Padmanabhan , Patterson Nicolle L. , Fields Gregg B. , Lindsey Merry L.
Published: August 2012

Since the discovery of tadpole collagenase in 1962, the matrix metalloproteinase (MMP) family has emerged as a significant proteinase group with recognized effects on the cardiovascular system. Over the last 40 years, many milestones have been achieved, from the identification of the first MMP, to the generation of the first MMP cDNA clone and null mouse, to the clinical approval of the first MMP inhibitor. Over the years, a few myths and misunderstandings have interwoven into the truths. In this review, we will discuss the major milestones of MMP research, as well as review the misinterpretations and misperceptions that have evolved. Clarifying the confusions and dispelling the myths will both provide a better understanding of MMP properties and functions and focus the cardiovascular field on the outstanding research questions that need to be addressed.
Effects of JAM-A deficiency or blocking antibodies on neutrophil migration and lung injury in a murine model of ALI
Authors: Lakshmi Sowmya P. , Reddy Aravind T. , Naik Meghna U. , Naik Ulhas P. , Reddy Raju C.
Published: August 2012

Transmigration of neutrophils (PMNs) from the vasculature into inflamed tissues, mediated by interactions between PMNs and adhesion molecules on endothelial cells, is an essential aspect of inflammation. The crucial adhesion molecules include junctional adhesion molecule (JAM)-A. Investigation of the role of this molecule in models of inflammatory disease has been limited, however, and results in different disease models have varied. No previous study has addressed JAM-A in lung disease or effects on oxidant stress and proinflammatory cytokines. We use JAM-A knockout mice and blocking antibodies to investigate the role of JAM-A in a murine model of acute lung injury (ALI). With either experimental system, we find that absence of JAM-A activity significantly reduces migration of PMNs into the alveolar space, with a resulting decrease in oxidative stress. However, there is no reduction in whole lung activity of PMN-associated myeloperoxidase, presumably reflecting the histologically observed retention of PMNs in lung tissue. Activity of these retained PMNs may account for our failure to find significant change in markers of lung oxidative stress or cytokine and chemokine levels in plasma, lung, and bronchoalveolar lavage fluid. We likewise see no JAM-A-related changes in markers of capillary permeability or lung injury. A similar lack of congruence between effects on PMN migration and tissue injury has been reported in other disease models and for other adhesion molecules in models of ALI. Our results thus confirm the crucial role of JAM-A in PMN transmigration but demonstrate that transmigration is not essential for other aspects of inflammation or for lung injury in ALI.
Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period
Authors: Carreras Alba , Kayali Foaz , Zhang Jing , Hirotsu Camila , Wang Yang , Gozal David
Published: August 2012

Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IHL) have not been extensively examined, it would appear that IHLand high-frequency intermittent hypoxia (IHH) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IHH(cycles of 90 s 6.4% O2and 90 s 21% O2during daylight), IHL(8% O2during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IHHand IHLdisplayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IHLand IHH, with IHLmanifesting the lowest insulin sensitivity compared with either IHHor CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IHL, IHH, and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IHL-exposed mice. Thus IHHand IHLelicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.
NADPH oxidase 4 mediates flow-induced superoxide production in thick ascending limbs
Authors: Hong Nancy J. , Garvin Jeffrey L.
Published: August 2012

We previously showed that luminal flow stimulates thick ascending limb (TAL) superoxide (O2−) production by stretching epithelial cells and increasing NaCl transport, and reported that the major source of flow-induced O2−is NADPH oxidase (Nox). However, the specific Nox isoform involved is unknown. Of the three isoforms expressed in the kidney—Nox1, Nox2, and Nox4—we hypothesized that Nox4 is responsible for flow-induced O2−production in TALs. Measurable flow-induced O2−production at physiological flow rates of 0, 5, 10, and 20 nl/min was 5 ± 1, 9 ± 2, 36 ± 6, and 66 ± 8 AU/s, respectively. RT-PCR detected mRNA for all three Nox isoforms in the TAL. The order of RNA abundance was Nox2 > Nox4 >>> Nox1. Since all three isoforms are expressed in TALs and pharmacological inhibitors are not selective, we used rats transduced with siRNA and knockout mice. Nox4 siRNA knocked down Nox4 mRNA expression by 63 ± 7% but did not reduce Nox1 or Nox2 mRNA. Flow-induced O2−was 18 ± 9 AU/s in TALs transduced with Nox4 siRNA compared with 77 ± 9 AU/s in tubules transduced with scrambled siRNA. Flow-induced O2−was 81 ± 5 AU/s in Nox2 knockout mice compared with 83 ± 13 AU/s in wild-type mice. In TALs transduced with Nox1 siRNA, flow-induced O2−was 82 ± 7 AU/s. We conclude that Nox4 mediates flow-induced O2−production in TALs.
Parathyroid hormone stimulates juxtaglomerular cell cAMP accumulation without stimulating renin release
Authors: Atchison Douglas K. , Harding Pamela , Cecilia Ortiz-Capisano M. , Peterson Edward L. , Beierwaltes William H.
Published: August 2012

Parathyroid hormone (PTH) is positively coupled to the generation of cAMP via its actions on the PTH1R and PTH2R receptors. Renin secretion from juxtaglomerular (JG) cells is stimulated by elevated intracellular cAMP, and every stimulus that increases renin secretion is thought to do so via increasing cAMP. Thus we hypothesized that PTH increases renin release from primary cultures of mouse JG cells by elevating intracellular cAMP via the PTH1R receptor. We found PTH1R, but not PTH2R, mRNA expressed in JG cells. While PTH increased JG cell cAMP content from (log10means ± SE) 3.27 ± 0.06 to 3.92 ± 0.12 fmol/mg protein ( P < 0.001), it did not affect renin release. The PTH1R-specific agonist, parathyroid hormone-related protein (PTHrP), also increased JG cell cAMP from 3.13 ± 0.09 to 3.93 ± 0.09 fmol/mg protein ( P < 0.001), again without effect on renin release. PTH2R receptor agonists had no effect on cAMP or renin release. PTHrP increased cAMP in the presence of both low and high extracellular calcium from 3.31 ± 0.17 to 3.83 ± 0.20 fmol/mg protein ( P < 0.01) and from 3.29 ± 0.18 to 3.63 ± 0.22 fmol/mg protein ( P < 0.05), respectively, with no effect on renin release. PTHrP increased JG cell cAMP in the presence of adenylyl cyclase-V inhibition from 2.85 ± 0.17 to 3.44 ± 0.14 fmol/mg protein ( P < 0.001) without affecting renin release. As a positive control, forskolin increased JG cell cAMP from 3.39 ± 0.13 to 4.48 ± 0.07 fmol/mg protein ( P < 0.01) and renin release from 2.96 ± 0.10 to 3.29 ± 0.08 ng ANG I·mg prot−1·h−1( P < 0.01). Thus PTH increases JG cell cAMP via non-calcium-sensitive adenylate cyclases without affecting renin release. These data suggest compartmentalization of cAMP signaling in JG cells.
Differential effects of inhaled methacholine on circumferential wall and vascular smooth muscle of third-generation airways in awake sheep
Authors: McLeod Damian , Parsons Gibbe , Gunther Robert , Quail Anthony , Cottee David , White Saxon
Published: August 2012

Evolution and natural selection ensure that specific mechanisms exist for selective airway absorption of inhaled atmospheric molecules. Indeed, nebulized cholinoceptor agonists used in asthma-challenge tests may or may not enter the systemic circulation. We examined the hypothesis that inhaled cholinoceptor agonists have selective access. Six sheep were instrumented under general anesthesia (propofol 5 mg/kg iv, 2-3% isoflurane–oxygen), each with pulsed-Doppler blood flow transducers mounted on the single bronchial artery and sonomicrometer probes mounted on the intrapulmonary third-generation lingula lobe bronchus. Continuous measurements were made of bronchial blood flow (Qbr), Qbr conductance (Cbr), bronchial hemicircumference (CIRCbr), and bronchial wall thickness (WALL THbr) in recovered, standing, awake sheep. Methacholine (MCh; 0.125–2.0 μg/kg iv), at the highest dose, caused a 233% rise in Qbr ( P < 0.05) and a 286% rise in Cbr ( P < 0.05). CIRCbr fell to 90% ( P < 0.05); WALL THbr did not change. In contrast, nebulized MCh (1–32 mg/ml), inhaled through a mask at the highest dose, caused a rise in ventilation and a rise in Qbr proportional to aortic pressure without change in Cbr. CIRCbr fell to 91% ( P < 0.01), and WALL THbr did not change. Thus inhaled MCh has access to cholinoceptors of bronchial circumferential smooth muscle to cause airway lumen narrowing but effectively not to those of the systemic bronchovascular circulation. It is speculated that the mechanism is selective neuroparacrine inhibition of muscarinic acetylcholine receptors (M3 bronchovascular cholinoceptors) by prostanoids released by intense MCh activation of epithelial and mucosal cells lining the airway.
Beyond establishing involvement: quantifying the contribution of anticipatory α- and β-band suppression to perceptual improvement with attention
Authors: van Ede Freek , Köster Malte , Maris Eric
Published: August 2012

Systems and cognitive neuroscience aim at understanding the neurophysiological mechanisms that underlie cognition and behavior. Many studies have revealed the involvement of many types of neural signals in diverse cognitive and behavioral phenomena. Here, we go beyond establishing such involvement and address two fundamental, yet largely unaddressed, questions: 1) exactly how much does a given neural signal contribute to a cognitive or behavioral phenomenon of interest; and 2) to what extent are distinct neural signals independently related to this phenomenon? We recorded brain activity using magnetoencephalography while human participants performed a cued somatosensory detection task. Using a novel method, we then quantified the contribution (in a predictive but not causal sense) of two well-established neural phenomena to the improvement in perception with attentional orienting. In our sample, the anticipatory suppression of extracranially recorded oscillatory α- and β-band amplitudes from contralateral primary somatosensory cortex could account for maximally 29% of the attention-induced improvement in tactile perception. In addition, although amplitude suppressions in the α- and β-frequency bands both contributed to this improvement, their contribution was largely shared. These data reveal the upper limit of the cognitive/behavioral relevance of this type of signal and show that at least 71% of the perceptual improvement with attention must be accounted for by other signals.
Current and Emerging Therapeutics for Cutaneous T-Cell Lymphoma: Histone Deacetylase Inhibitors
Authors: Rodd Annabelle L. , Ververis Katherine , Karagiannis Tom C.
Published: August 2012

Cutaneous T-cell lymphoma is a term that encompasses a spectrum of non-Hodgkin’s T-cell lymphomas with primary manifestations in the skin. It describes a heterogeneous group of neoplasms that are characterised by an accumulation of malignant T cells of the CD4 phenotype that have the propensity to home and accumulate in the skin, lymph nodes, and peripheral blood. The two most common variants of cutaneous T-cell lymphoma include mycosis fungoides and the leukemic variant, the Sézary syndrome. While numerous treatments are available for cutaneous T-cell lymphoma and have shown to have success in those with patch and plaque lesions, for those patients with tumour stage or lymph node involvement there is a significant decline in response. The relatively new therapeutic option with the use of histone deacetylase inhibitors is being advanced in the hope of decreasing morbidity and mortality associated with the disease. Histone deacetylase inhibitors have been shown to induce changes in gene expression, affecting cell cycle regulation, differentiation, and apoptosis. The aim of this paper is to discuss CTCL in the context of advances in CTCL treatment, specifically with HDAC inhibitors.
The Real Economics of Climate Engineering
Authors: Klepper Gernot , Rickels Wilfried
Published: August 2012

In 2008 Scott Barrett wrote a paper on “The incredible economics of geoengineering” in which he argued that the potentially low cost of climate engineering (CE) measures together with the quick response of the earth’s temperature to such interventions will change the whole debate about the mitigation of climate change. Whereas Barrett was mostly focusing on the cost of running CE measures, we point out that several determinants of overall economic cost like price or external effects are not yet sufficiently accounted for and that the question of dynamic efficiency is still unresolved. Combining the existing theoretical investigations about the topic from the literature, we show that even though these new measures provide new options to deal with climate change, several of them might also reduce our scope of action. Consequently, we suggest that economic research should shift its focus to portfolios of CE measures and put more emphasis on those measures which control atmospheric carbon concentration and therefore allow extending our scope of action. Additionally, economic research should address the question of phase-in and phase-out scenarios for measures which directly influence the radiation balance.
Mycoplasma pneumoniae-Induced-Stevens Johnson Syndrome: Rare Occurrence in an Adult Patient
Authors: Rasul Samad , Farhat Faria , Endailalu Yared , Tabassum Khan Fatima , Poddar Vishal
Published: August 2012

Stevens-Johnson syndrome (SJS) is an uncommon occurrence inMycoplasma pneumoniae(M. pneumoniae) infection (1–5%) and has been mainly reported in children and young adults. We present a case of SJS in a 32-year-old male induced byM. pneumoniaeinfection. This patient presented with fever, cough, and massive occupation of mucus membranes with swelling, erythema, and necrosis accompanied by a generalized cutaneous rash. He clinically responded after treatment with antibiotics and IVIG. SJS is usually a drug-induced condition; however,M. pneumoniaeis the commonest infectious cause and should be considered in the differential diagnosis.
Langerhans Cell Histiocytosis of the Cranial Base: Is Low-Dose Radiotherapy Effective?
Authors: Meyer Andreas , Stark Michael , Karstens Johann H. , Christiansen Hans , Bruns Frank
Published: August 2012

Introduction. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology with different clinical features. A standardised treatment has not been established so far.Case Report. We report a case of a 28-year-old patient who initially presented with hypesthesia of the fifth cranial nerve and pain of the left ear. Diagnosis showed a tumour localised in the cranial base with a maximum diameter of 4.1 cm. The diagnosis of LCH was confirmed histologically by biopsy. Diagnostic workup verified the cranial lesion as the sole manifestation of LCH. A total dose of 9 Gy (single dose 1.8 Gy) was delivered. The symptoms dissolved completely within 6 months after radiation; repeated CT and MRI scans revealed a reduction in size of the lesion and a remineralisation of the bone. After a followup of 13 years the patient remains free of symptoms without relapse or any side effects from therapy.Discussion. Due to the indolent course of the disease with a high rate of spontaneous remissions the choice of treatment strongly depends on the individual clinical situation. In the presented case low-dose radiotherapy was sufficient to obtain long-term local control in a region with critical structures and tissues.
Hair Dye Poisoning in a Paediatric Patient
Authors: Chandran Jolly , Manners Rimi , Agarwal Indira , Ebenezer Kala
Published: August 2012

Hair dye ingestion with suicidal intention has increased among rural Indian population and is associated with significant mortality. We report a teenager who presented with cervicofacial edema, respiratory distress, rhabdomyolysis, and myocarditis after ingesting the hair dye Super Vasmol 33. Early and supportive treatment can prevent morbidity and mortality.
RAP80 Is Critical in Maintaining Genomic Stability and Suppressing Tumor Development
Authors: Yin Zhengyu , Menendez Daniel , Resnick Michael A. , French John E. , Janardhan Kyathanahalli S. , Jetten Anton M.
Published: August 2012

The ubiquitin interaction motif-containing protein RAP80 was recently found to play a key role in DNA damage response (DDR) signaling by facilitating the translocation of several DDR mediators, including BRCA1, to ionizing irradiation (IR)-induced foci. In this study, we examine the effect of the loss of RAP80 on genomic stability and the susceptibility to cancer development in RAP80 null (RAP80−/−) mice. RAP80−/− mice are viable and did not exhibit any apparent developmental defects. Mouse embryonic fibroblasts (MEF) derived from RAP80−/− mice underwent premature senescence compared with wild-type (WT) MEFs, were more sensitive to IR, and exhibited a higher level of spontaneous and IR-induced genomic instability. RAP80−/− thymocytes were more sensitive to IR-induced cell death than WT thymocytes. RAP80−/− mice were more susceptible to spontaneous lymphoma development and the development of 7,12-dimethylbenz(a)anthracene-induced mammary gland tumors. Moreover, the loss of RAP80 accelerated tumor formation in both p53−/− and p53+/− mice. Our data indicate that RAP80-deficiency promotes genomic instability and causes an increase in cancer risk consistent with the concept that RAP80 exhibits a tumor suppressor function. Cancer Res; 72(19); 5080–90. ©2012 AACR.
Src Inhibition with Saracatinib Reverses Fulvestrant Resistance in ER-Positive Ovarian Cancer Models In Vitro and In Vivo
Authors: Simpkins Fiona , Hevia-Paez Pedro , Sun Jun , Ullmer Wendy , Gilbert Candace A. , da Silva Thiago , Pedram Ali , Levin Ellis R. , Reis Isildinha M. , Rabinovich Brian , Azzam Diana , Xu Xiang-Xi , Ince Tan A. , Yang Ji-Yeon , Verhaak Roel G.W. , Lu Yiling , Mills Gordon B. , Slingerland Joyce M.
Published: August 2012

Purpose: More effective, less toxic treatments for recurrent ovarian cancer are needed. Although more than 60% of ovarian cancers express the estrogen receptor (ER), ER-targeted drugs have been disappointing due to drug resistance. In other estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell-cycle progression. Because Src is activated in most ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent antiestrogen resistance.

Experimental Design: ER and Src were assayed in 338 primary ovarian cancers. Dual ER and Src blockade effects on cell cycle, ER target gene expression, and survival were assayed in ERα+ ovarian cancer lines, a primary human ovarian cancer culture in vitro, and on xenograft growth.

Results: Most primary ovarian cancers express ER. Src activity was greater in ovarian cancer lines than normal epithelial lines. Estrogen activated Src, ER-Src binding, and ER translocation from cytoplasm to nucleus. Estrogen-mediated mitogenesis was via ERα, not ERβ. While each alone had little effect, combined saracatinib and fulvestrant increased p27 and inhibited cyclin E-Cdk2 and cell-cycle progression. Saracatinib also impaired induction of ER-target genes c-Myc and FOSL1; this was greatest with dual therapy. Combined therapy induced autophagy and more effectively inhibited ovarian cancer xenograft growth than monotherapy.

Conclusions: Saracatinib augments effects of fulvestrant by opposing estrogen-mediated Src activation and target gene expression, increasing cell-cycle arrest, and impairing survival, all of which would oppose antiestrogen resistance in these ER+ ovarian cancer models. These data support further preclinical and clinical evaluation of combined fulvestrant and saracatinib in ovarian cancer. Clin Cancer Res; 18(21); 5911–23. ©2012 AACR.
Intracerebral CpG Immunotherapy with Carbon Nanotubes Abrogates Growth of Subcutaneous Melanomas in Mice
Authors: Fan Haitao , Zhang Ian , Chen Xuebo , Zhang Leying , Wang Huaqing , Da Fonseca Anna , Manuel Edwin R. , Diamond Don J. , Raubitschek Andrew , Badie Behnam
Published: August 2012

Purpose: Recently, we showed that intratumoral delivery of low-dose, immunostimulatory CpG oligodeoxynucleotides conjugated with carbon nanotubes (CNT-CpG) was more effective than free CpG and not only eradicated intracranial (i.c.) gliomas but also induced antitumor immunity that protected mice from subsequent i.c. or systemic tumor rechallenge. Here, we examined whether the same “intracerebral immunotherapy” strategy could be applied to the treatment of metastatic brain tumors.

Experimental Design: Mice with both i.c. and s.c. melanomas were injected intratumorally with CNT-CpG into either location. Antitumor responses were assessed by flow cytometry, bioluminescent imaging, and animal survival.

Results: When given s.c., CNT-CpG response was mostly local, and it only modestly inhibited the growth of i.c. melanomas. However, i.c. CNT-CpG abrogated the growth of not only brain but also s.c. tumors. Furthermore, compared with s.c. injections, i.c. CNT-CpG elicited a stronger inflammatory response that resulted in more potent antitumor cytotoxicity and improved in vivo trafficking of effector cells into both i.c. and s.c. tumors. To investigate factors that accounted for these observations, CNT-CpG biodistribution and cellular inflammatory responses were examined in both tumor locations. Intracranial melanomas retained the CNT-CpG particles longer and were infiltrated by Toll-like receptor (TLR-9)–positive microglia. In contrast, myeloid-derived suppressive cells were more abundant in s.c. tumors. Although depletion of these cells before s.c. CNT-CpG therapy enhanced its cytotoxic responses, antitumor responses to brain melanomas were unchanged.

Conclusions: These findings suggest that intracerebral CNT-CpG immunotherapy is more effective than systemic therapy in generating antitumor responses that target both brain and systemic melanomas. Clin Cancer Res; 18(20); 5628–38. ©2012 AACR.