bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative methylation analysis reveals gender and age differences in p16INK4a hypermethylation in hepatitis B virus‐related hepatocellular carcinoma
Authors: Wang Yongfeng , Cheng Jin , Xu Chunhui , Liu Shuang , Jiang Suzhen , Xu Qiang , Chen Xiangmei , Zhuang Hui , Lu Fengmin
Published: December 2011

Background

Frequent promoter hypermethylation of the inhibitors in either Rb or p53 pathways is associated with the hepatocellular carcinoma (HCC) development.

Objective

To quantitatively assess the gradual changes of the promoter methylation of p14ARF, p15INK4b, p16INK4a and CCND2 genes in hepatitis B virus (HBV) infection‐related HCC.

Methods

A total of 118 pairs of tumour and their corresponding non‐tumour tissues were collected from HCC patients with evidence of HBV infection. The promoter methylation status was analysed by combined DNA methylation‐sensitive and methylation‐dependent restriction endonuclease digestion, followed by subsequential quantitative PCR assay.

Results

Promoter hypermethylation frequencies were gradually increased from 6.25% in normal liver tissues to 21.19% in adjacent non‐tumour and to 40.68% in tumour tissues for p16INK4a (P = 0.000), and from none to 10.20% and to 29.59% for CCND2 (P = 0.001). The hypermethylation intensities in HCC tissues were also significantly increased (P = 0.0018 for p16INK4a, P = 0.0001 for CCND2). Altogether, 48.93% cases were found with increased hypermethylation intensity of either p16INK4a and/or CCND2 promoter in tumour tissues, compared with their matched non‐tumour tissues. In addition, tumour tissue p16INK4a promoter hypermethylation was significantly higher in male than that in female gender patients in frequency (P = 0.041) and was significantly increased in patients older than 50 years of age in intensity (P = 0.0021). No hypermethylation of p14ARF or p15INK4b was found.

Conclusion

Our study demonstrated that from normal liver to the adjacent cirrhotic liver and to the HCC tissues, p16INK4a hypermethylation was gradually increased both in frequency and in intensity, such increase might be gender and age related.
Intervention in Aboriginal Life
Authors: Martin John Hilary
Published: December 2011

John Howard the then Prime Minister of Australia introduced a series of measures (June 2007) to regulate the life of Aboriginal peoples in the Northern Territory, an action that became known as the Intervention. The measures were introduced as emergency measures designed to control the widespread physical and sexual abuse of children, the excessive use of alcohol, poor levels of education and unemployment rife among Aboriginal people in the Territory according to a government sponsored report, Little Children are Sacred. The local councils of aboriginal communities were immediately dissolved, their property acquired by compulsory leases for five years and business managers appointed to administer them. After an initial occupation by army units and police to stabilize the situation in Aboriginal communities and settlements, the Federal government introduced a number of measures designed to channel welfare money for purchase of wholesome food, to limit access to alcohol and it made a commitment to refurbish schools and clinics and to build houses to ease overcrowding. These were all good things to do and cost the government hundreds of millions of dollars, but were imposed from without in a bureaucratic manner with little consultation of local people. Construction programs were conducted largely by non-aboriginal workers and school curricula were not revised with an eye to Aboriginal cultural needs or interests. The ancient culture of Aboriginal people depends upon the land, family relationship and upon the Dreaming. The bureaucracy dealt with Aboriginal communities as if it were dealing with a particularly difficult city suburb that required a new master plan. Instead of this, Aboriginal people must resolve their communal problems in their own way. For that to happen there is a need to encourage initiative and creativity and conversion of life. The Intervention and what followed did not deal well with the cultural side of its program and it did more to smother Aboriginal initiative than to encourage it.
The effects of flood defences on riparian vegetation species richness and abundance
Authors: Pettifer Elizabeth , Kay Paul
Published: December 2011

It is widely recognised that flood disturbance has important consequences for the biodiversity of riparian zones and that inundation allows nutrients and organic matter to be exchanged and recycled between aquatic and terrestrial ecosystems. Previous research has focused on the impacts of dams on riparian biodiversity, with little consideration given to the impacts of flood defences. The current study investigated the extent to which the presence and age of flood defences controls riparian plant richness and abundance. Sites without flood defences were found to have significantly higher species richness and abundance. In contrast, flood defence age was found to have little impact although turnover was high between sites with old and new defences. Flood management should therefore focus on more sustainable options that work with natural processes where possible, such as washlands.
Efficacy and safety of repaglinide vs nateglinide for treatment of Japanese patients with type 2 diabetes mellitus
Authors: Kawamori Ryuzo , Kaku Kohei , Hanafusa Toshiaki , Kashiwabara Daisuke , Kageyama Shigeru , Hotta Nigishi
Published: December 2011

Aims/Introduction:  Repaglinide is a short‐acting insulin secretagogue. We assessed the efficacy and safety of repaglinide in comparison with nateglinide in Japanese patients with type 2 diabetes previously treated with diet and exercise.

Materials and Methods:  In this 16‐week randomized, multicenter, double‐blind, parallel‐group, active‐controlled superiority trial, Japanese patients with type 2 diabetes and glycated hemoglobin (HbA1c) of ≥6.9 and ≤9.4% were enrolled. Patients were randomly assigned to receive 0.5 mg repaglinide (n = 64) or 90 mg nateglinide (n = 66) three times a day. The primary end‐point was changes in HbA1c from baseline to the end of treatment.

Results:  Mean reductions of HbA1c were significantly greater for the repaglinide group than the nateglinide group (−1.17 ± 0.62 vs −0.81 ± 0.39%, P < 0.001). The target HbA1c values of <6.9% were achieved by 75.0% of the repaglinide group vs 59.1% for nateglinide. Mean changes in fasting plasma glucose also showed significantly greater efficacy for repaglinide than nateglinide (−26.0 ± 20.9 vs −18.3 ± 17.8 mg/dL, P < 0.001). There were no differences in the adverse event rates between the repaglinide and the nateglinide group, by 57.8% (37/64) and 60.6% (40/66), respectively. Incidences of hypoglycemic symptoms were 17.2% (11/64, 28 events) in the repaglinide group and 6.1% (4/66, 20 events) in the nateglinide group, respectively.

Conclusions:  In type 2 diabetic patients treated with diet and exercise, repaglinide monotherapy gives greater glycemic improvement than nateglinide monotherapy in reducing HbA1c and fasting plasma glucose values after 16 weeks. This trial was registered with JapicCTI (no. JapicCTI‐080521). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00188.x, 2011)
Flow Pattern and Slug Dynamics Around a Flow Splitter
Authors: Alamu M. B. , Azzopardi B. J.
Published: December 2011

Application of dividing junction in sub-sea separation of a hydrocarbon well stream is becoming increasingly popular across the petroleum industry. They are often used in stage separation of a hydrocarbon well stream to reduce process load on a primary separator. Where the diameters of the pipes making up the junction are small, it is of particular interest to nano multiphase flow technology (NMFT) currently being advocated. While there is a body of data for small diameter dividing junctions, it is almost exclusively for air-water where the pattern before flow and after the junction in the vertical segment of the pipe is usually unchanged. Here, new data for air and more viscous liquid are presented. They have been acquired from electrical resistance measurements made between pairs of flush-mounted ring conductance probes located around the junction. Liquid phase viscosities were varied systematically between 1 mPa·s (water) and 36 mPa·s (water-glycerol mixture). The implemented test matrix varied between 0 – 32 m/s for gas superficial velocity and 0.003 – 1.3 m/s for liquid superficial velocity respectively. The internal pipe diameter making up the junction is 5 mm. The time varying void fraction obtained has been used to obtain probability density functions (PDF) to characterize the flow. PDF exhibit lower peaks and a marked shift in the direction of decreasing void fraction for more viscous liquid. Flow structure frequency was extracted from a detailed spectrum analysis (PSD) based on the fluctuation of void wave signals with time. The result shows that the dominant frequency of the flow structure increases as liquid viscosity increases. Analysis of the measured phase split data reveals additional flow assurance details. This study shows the effect of liquid viscosity becomes significant only when the gas taken off exceeds a threshold of 0.40. The plot of the liquid hold-up against the mixture velocity fingerprints churn-annular transition boundary around a gas superficial velocity of 15 m/s. The flow pattern approaching the junction changes after leaving the junction in the vertical run arm as liquid viscosity increases; however, an increase in liquid viscosity has no effect on flow pattern in the horizontal side arm.
Nano-Enhanced Drilling Fluids: Pioneering Approach to Overcome Uncompromising Drilling Problems
Authors: Abdo J. , Haneef M. Danish
Published: December 2011

The idea of pushing the limits of drilling oil and gas wells by improving drilling fluids for undemanding and cost efficient drilling operations by extracting advantage from the wonders of nanotechnology forms the basis of the work presented here. Foremost, in order to highlight the significance of reducing the size distribution of particles, new clay ATR which has a chain like structure and offers enormous surface area and increased reactivity was tested in different sizes that were chemically and mechanically milled. Bentonite which is a commonly used drilling fluid additive was also tested in different particle size distribution (PSD) and rheological properties were tested. Significant reduction in viscosity with small sized particles was recorded. The tested material called ATR throughout this paper is shown to offer better functionality than bentonite without the requirement of other expensive additives. Experiments were performed with different size distributions and compositions and drastic changes in rheological properties are observed. A detailed investigation of the shear thinning behavior was also carried out with ATR samples in order to confirm its functionality for eliminating the problem of mechanical and differential pipe sticking, while retaining suitable viscosity and density for avoidance of problems like lost circulation, poor hole cleaning and inappropriate operating hydrostatic pressures.
Isothermal Modeling of Meniscus Oscillation in the Continuous Strip Casting Process
Authors: Wilcox Kevin W. , Holloway A. Gordon L. , Gerber Andrew G.
Published: December 2011

In the continuous strip casting process a meniscus forms a compliant boundary between the casting nozzle and transporting conveyor. Movement of this meniscus during casting has been shown to create surface defects, which require extensive cold work to remove and limit the minimum thickness for which sections may be cast. This paper discusses experimental work conducted to test an analytical model of the meniscus oscillation. A high frame rate shadowgraph technique was used on an isothermal water model of the casting process to observe meniscus motion, and thus allow the calculation of meniscus frequency, amplitude, contact points and contact angles. Both natural frequency and flow excited tests were conducted. Natural frequency tests were also conducted using mercury which has a nonwetting contact angle typical of molten metals. The experimental results were found to be in good agreement with the predictions of theory for both wetting and nonwetting conditions. The experimentally verified analytical model for meniscus motion is valuable to the design of a continuous casting process because it describes the effect of geometrical parameters on meniscus motion and thus provides an opportunity to mitigate the effects of boundary motion on surface quality.
High-Resolution View of the Yeast Meiotic Program Revealed by Ribosome Profiling
Authors: Brar Gloria A. , Yassour Moran , Friedman Nir , Regev Aviv , Ingolia Nicholas T. , Weissman Jonathan S.
Published: December 2011

Monitoring Meiosis

During meiosis, or in yeast sporulation, haploid cells are generated from diploid cells.

Brar
et al.

(p.
552
, published online 22 December) performed a detailed analysis of messenger RNA (mRNA) abundance and protein synthesis over the course of sporulation. The production of most proteins was tightly regulated both at the mRNA level and by translational control. An unexpected complexity was observed as the cell passed through this key developmental transition, including increases in noncanonical translation from upstream regions of known RNA transcripts, which appear to be important in translational control.
Novel Bacterial Isolate from Permian Groundwater, Capable of Aggregating Potential Biofuel-Producing Microalga Nannochloropsis oceanica IMET1
Authors: Wang Hui , Laughinghouse Haywood D. , Anderson Matthew A. , Chen Feng , Willliams Ernest , Place Allen R. , Zmora Odi , Zohar Yonathan , Zheng Tianling , Hill Russell T.
Published: December 2011

Increasing petroleum costs and climate change have resulted in microalgae receiving attention as potential biofuel producers. Little information is available on the diversity and functions of bacterial communities associated with biofuel-producing algae. A potential biofuel-producing microalgal strain,
Nannochloropsis oceanica
IMET1, was grown in Permian groundwater. Changes in the bacterial community structure at three temperatures were monitored by two culture-independent methods, and culturable bacteria were characterized. After 9 days of incubation,
N. oceanica
IMET1 began to aggregate and precipitate in cultures grown at 30°C, whereas cells remained uniformly distributed at 15°C and 25°C. The bacterial communities in cultures at 30°C changed markedly. Some bacteria isolated only at 30°C were tested for their potential for aggregating microalgae. A novel bacterium designated HW001 showed a remarkable ability to aggregate
N. oceanica
IMET1, causing microalgal cells to aggregate after 3 days of incubation, while the total lipid content of the microalgal cells was not affected. Direct interaction of HW001 and
N. oceanica
is necessary for aggregation. HW001 can also aggregate the microalgae
N. oceanica
CT-1,
Tetraselmis suecica
, and
T. chuii
as well as the cyanobacterium
Synechococcus
WH8007. 16S rRNA gene sequence comparisons indicated the great novelty of this strain, which exhibited only 89% sequence similarity with any previously cultured bacteria. Specific primers targeted to HW001 revealed that the strain originated from the Permian groundwater. This study of the bacterial communities associated with potential biofuel-producing microalgae addresses a little-investigated area of microalgal biofuel research and provides a novel approach to harvest biofuel-producing microalgae by using the novel bacterium strain HW001.
Cellular Response of Campylobacter jejuni to Trisodium Phosphate
Authors: Riedel Charlotte Tandrup , Cohn Marianne Thorup , Stabler Richard A. , Wren Brendan , Brøndsted Lone
Published: December 2011

The highly alkaline compound trisodium phosphate (TSP) is used as an intervention to reduce the load of
Campylobacter
on poultry meat in U.S. poultry slaughter plants. The aim of the present study was to investigate the cellular responses of
Campylobacter jejuni
NCTC11168 when exposed to sublethal concentrations of TSP. Preexposure of
C. jejuni
to TSP resulted in a significant increase in heat sensitivity, suggesting that a combined heat and TSP treatment may increase reduction of
C. jejuni
. A microarray analysis identified a limited number of genes that were differently expressed after sublethal TSP exposure; however, the response was mainly associated with ion transport processes.
C. jejuni
NCTC11168
nhaA1
(Cj1655c) and
nhaA2
(Cj1654c), which encode orthologues to the
Escherichia coli
NhaA cation/proton antiporter, were able to partially restore TSP, alkaline, and sodium resistance phenotypes to an
E. coli
cation/proton antiporter mutant. In addition, inhibition of
r
esistance-
n
odulation-cell
d
ivision (RND) multidrug efflux pumps by the inhibitor PaβN (Phe-Arg β-naphthylamide dihydrochloride) decreased tolerance to sublethal TSP. Therefore, we propose that NhaA1/NhaA2 cation/proton antiporters and RND multidrug efflux pumps function in tolerance to sublethal TSP exposure in
C. jejuni
.
Impact of Relative Humidity and Collection Media on Mycobacteriophage D29 Aerosol
Authors: Liu Keyang , Wen Zhanbo , Li Na , Yang Wenhui , Wang Jie , Hu Lingfei , Dong Xiaokai , Lu Jianchun , Li Jinsong
Published: December 2011

This study was conducted to evaluate the effect of aerosol generation, methods of sampling, storage conditions, and relative humidity on the culturability of the mycobacteriophage D29. The lytic phage D29 can kill
Mycobacterium tuberculosis
, and the phage aerosol can be treated as a potential tool for tuberculosis treatment. The culturability of D29 was tested using a test chamber designed for the bioaerosols research against three spray liquids (deionized water, phosphate-buffered saline [PBS], and normal saline), four collection media (suspension medium [SM], nutrient broth, PBS, and deionized water), two sampling systems (the all-glass impinger AGI-30 and the Biosampler) and across a range of humidities (20 to 90%). The effect of storage conditions on the culturability of collected sample was also evaluated for the AGI-30 impinger. The results proved that viable phage D29 particles generated by deionized water were approximately 30- and 300-fold higher than PBS and normal saline, respectively. As collection media, SM buffer and nutrient broth were observed to yield a higher number of plaques compared to PBS and deionized water. No difference was observed in collection efficiency between AGI-30 and Biosampler with two detection methods (culture-based technique and real-time PCR). The culturability of collected D29 in SM buffer or nutrient broth can be maintained up to 12 h irrespective of storage temperature. Relative humidity was found to strongly influence airborne D29 culturability which is 2- to 20-fold higher in low humidity (25%) than medium (55%) or high (85%) humidity. This research will help identify the optimal means for the application of D29 aerosol in animal inhalation experiments.
Endovascular treatment of intracranial aneurysms in Loeys–Dietz syndrome
Authors: Levitt Michael R , Morton Ryan P , Mai Jeffrey C , Ghodke Basavaraj , Hallam Danial K
Published: December 2011

Background

Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by extensive arterial aneurysms. The successful clipping of intracranial aneurysms in patients with LDS has been reported in a limited number of patients but endovascular treatment of intracranial aneurysms in LDS has never before been described. The first successful cases of endovascular management of five intracranial aneurysms in two patients with LDS are reported.

Clinical presentation

The first patient was an asymptomatic 45-year-old woman with LDS and two incidentally discovered, unruptured wide necked aneurysms (6×5 mm and 4×2 mm) arising from the ophthalmic segment of the left internal carotid artery. Both aneurysms were successfully embolized via Neuroform stent assisted coiling. The second patient was an asymptomatic middle 40s woman with LDS found to have an unruptured anterior communicating artery aneurysm (7×4 mm) as well as two ophthalmic segment aneurysms (2.5×3.7 mm and 2.9×3.5 mm). All three aneurysms were successfully embolized via Neuroform stent assisted coiling in two staged procedures. There were no periprocedural complications in either patient. Long term follow-up imaging demonstrated durable embolization in all aneurysms in both patients.

Conclusion

This is the first reported case series of endovascular management of intracranial aneurysms in the setting of LDS. The endovascular approach was safe, effective and durable in all aneurysms in both patients, and should be considered when treating patients with LDS and intracranial aneurysms.
Frameless multimodal image guidance of localized convection-enhanced delivery of therapeutics in the brain
Authors: van der Bom Imramsjah M J , Moser Richard P , Gao Guanping , Sena-Esteves Miguel , Aronin Neil , Gounis Matthew J
Published: December 2011

Introduction

Convection-enhanced delivery (CED) has been shown to be an effective method of administering macromolecular compounds into the brain that are unable to cross the blood-brain barrier. Because the administration is highly localized, accurate cannula placement by minimally invasive surgery is an important requisite. This paper reports on the use of an angiographic c-arm system which enables truly frameless multimodal image guidance during CED surgery.

Methods

A microcannula was placed into the striatum of five sheep under real-time fluoroscopic guidance using imaging data previously acquired by cone beam computed tomography (CBCT) and MRI, enabling three-dimensional navigation. After introduction of the cannula, high resolution CBCT was performed and registered with MRI to confirm the position of the cannula tip and to make adjustments as necessary. Adeno-associated viral vector-10, designed to deliver small-hairpin micro RNA (shRNAmir), was mixed with 2.0 mM gadolinium (Gd) and infused at a rate of 3 μl/min for a total of 100 μl. Upon completion, the animals were transferred to an MR scanner to assess the approximate distribution by measuring the volume of spread of Gd.

Results

The cannula was successfully introduced under multimodal image guidance. High resolution CBCT enabled validation of the cannula position and Gd-enhanced MRI after CED confirmed localized administration of the therapy.

Conclusion

A microcannula for CED was introduced into the striatum of five sheep under multimodal image guidance. The non-alloy 300 μm diameter cannula tip was well visualized using CBCT, enabling confirmation of the position of the end of the tip in the area of interest.
INCONSISTENCES IN INTERACTING AGEGRAPHIC DARK ENERGY MODELS
Authors: SUN CHENG-YI , SONG YU
Published: December 2011

It is found that the origin agegraphic dark energy tracks the matter in the matter-dominated epoch and then the subsequent dark-energy-dominated epoch becomes impossible. It is argued that the difficulty can be removed when the interaction between the agegraphic dark energy and dark matter is considered. In the note, by discussing three different interacting models, we find that the difficulty still stands even in the interacting models. Furthermore, we find that in the interacting models, there exists the other serious inconsistence that the existence of the radiation/matter-dominated epoch contradicts the ability of agegraphic dark energy in driving the accelerated expansion. The contradiction can be avoided in one of the three models if some constraints on the parameters hold.
IMPROVED STABILITY ESTIMATES FOR GENERAL SCALAR CONSERVATION LAWS
Authors: LÉCUREUX-MERCIER MAGALI
Published: December 2011

We consider the general scalar balance law ∂tu + Div f(t, x, u) = F(t, x, u) in several space dimensions and improve the results of Colombo, Mercier and Rosini who gave an estimate of the dependence of the solutions in terms of the flux f and the source F. The improvement is two-fold: first, the expression of the coefficients in these estimates are sharper and, second, we eliminate some regularity hypotheses, and thus extend significantly the applicability of these estimates.
Yes-associated protein is involved in proliferation and differentiation during postnatal liver development
Authors: Septer Seth , Edwards Genea , Gunewardena Sumedha , Wolfe Andy , Li Hua , Daniel James , Apte Udayan
Published: December 2011

It is known that the liver undergoes size increase and differentiation simultaneously during the postnatal period. Cells in the liver undergo a period of well-controlled proliferation to achieve the adult liver-to-body weight ratio. The postnatal liver growth is also accompanied by simultaneous hepatic differentiation. However, the mechanisms of liver size regulation and differentiation are not completely clear. Herein we report that yes-associated protein (Yap), the downstream effector of the Hippo Kinase signaling pathway, plays a role in liver size regulation and differentiation during the postnatal liver growth period. Postnatal liver growth was studied in C57BL/6 mice over a time course of postnatal days (PND) 0- 30. Analysis of nuclear Yap by Western blot indicated peak Yap activation between PND15–20, which coincided with increased cyclin D1 expression and liver cell proliferation. Analysis of postnatal liver development in Yap+/− mice revealed a significant decrease in the liver-to-body weight ratio compared with Yap+/+ mice at PND15 and -30. Yap+/− mice exhibited a significant decrease in postnatal liver cell proliferation, but no change in apoptosis was observed. Furthermore, global gene expression analysis of Yap+/− livers revealed a role of Yap in regulation of genes involved in bile acid metabolism, retinoic acid metabolism, ion transport, and extracellular matrix proteins. Taken together, these data indicate that Yap plays a role in both cell proliferation and possibly in hepatic differentiation during postnatal liver development.
Altered spatial calcium regulation enhances electrical heterogeneity in the failing canine left ventricle: implications for electrical instability
Authors: Iyer Vivek , Heller Victoria , Armoundas Antonis A.
Published: December 2011

Myocytes across the left ventricular (LV) wall of the mammalian heart are known to exhibit heterogeneity of electrophysiological properties; however, the transmural variation of cellular electrophysiology and Ca2+ homeostasis in the failing LV is incompletely understood. We studied action potentials (APs), the L-type calcium (Ca2+) current ( ICa,L), and intracellular Ca2+ transients ([Ca2+]i) of subendocardial (Endo), midmyocardial (Mid), and subepicardial (Epi) tissue layers in the canine normal and tachycardia pacing-induced failing left ventricles. Heart failure (HF) was associated with significant prolongation of the AP duration in Mid myocytes. There were no differences in ICa,L density in normal Endo, Mid, and Epi myocytes, whereas in the failing heart, ICa,L density was downregulated by 45% and 26% (at +10 mV) in Endo and Mid myocytes, respectively. The rates of sarcoplasmic reticulum (SR) Ca2+ release and decay of the [Ca2+]i were slowed, and the amplitude of the [Ca2+]i was depressed in Endo and Epi myocytes isolated from failing, compared with normal, hearts. Experiments in sodium (Na+)-free solutions showed that Epi and Mid myocytes of the failing ventricle exhibit a greater reliance on the Na+-Ca2+ exchanger to remove cytosolic Ca2+ than myocytes isolated from normal hearts. Simulation studies in Endo, Mid, and Epi canine myocytes demonstrate the importance of L-type current density and SR Ca2+ uptake in modulating the potentially arrhythmogenic repolarization in HF. In conclusion, these results demonstrate that spatially heterogeneous decreases in ICa,L and defective cytosolic Ca2+ removal contribute to the altered [Ca2+]i and AP profiles across the canine failing LV. These distinct electrophysiological features in myocytes from a failing heart contribute to a characteristic electrogram arising from increased dispersion of refractoriness across the LV, which may result in significant arrhythmogenic sequellae.
Ventilatory and cardiac responses to hypoxia at submaximal exercise are independent of altitude and exercise intensity
Authors: Lhuissier François J. , Brumm Maxime , Ramier Didier , Richalet Jean-Paul
Published: December 2011

The hypoxic exercise test combining a 4,800-m simulated altitude and a cycloergometer exercise at 30% of normoxic maximal aerobic power (MAP) is used to evaluate the individual chemosensitivity to hypoxia in submaximal exercise conditions. This test allows the calculation of three main parameters: the decrease in arterial oxygen saturation induced by hypoxia at exercise (ΔSae) and the ventilatory (HVRe) and cardiac (HCRe) responses to hypoxia at exercise. The aim of this study was to determine the influence of altitude and exercise intensity on the values of ΔSae, HVRe, and HCRe. Nine subjects performed hypoxic tests at three simulated altitudes (3,000 m, 4,000 m, and 4,800 m) and three exercise intensities (20%, 30%, and 40% MAP). ΔSae increased with altitude and was higher for 40% MAP than for 20% or 30% ( P < 0.05). For a constant heart rate, the loss in power output induced by hypoxia, relative to ΔSae, was independent of altitude (4,000–4,800 m) and of exercise intensity. HVRe and HCRe were independent of altitude (3,000–4,800 m) and exercise intensity (20%-40% MAP). Moreover, the intraindividual variability of responses to hypoxia was lower during moderate exercise than at rest ( P < 0.05 to P < 0.001). Therefore, we suggest that HVRe and HCRe are invariant parameters that can be considered as intrinsic physiological characteristics of chemosensitivity to hypoxia.
Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults
Authors: Eisenach John H. , Gullixson Leah R. , Kost Susan L. , Joyner Michael J. , Turner Stephen T. , Nicholson Wayne T.
Published: December 2011

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue−1·min−1) were measured before and after endothelial NO synthase inhibition with NG-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh − FBF baseline) − (FBF AChL-NMMA − FBF baselineL-NMMA)]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue−1·min−1 for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue−1·min−1 for the women ( P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.
SMYD3 Promotes Cancer Invasion by Epigenetic Upregulation of the Metalloproteinase MMP-9
Authors: Cock-Rada Alicia M. , Medjkane Souhila , Janski Natacha , Yousfi Nadhir , Perichon Martine , Chaussepied Marie , Chluba Johanna , Langsley Gordon , Weitzman Jonathan B.
Published: December 2011

Upregulation of the matrix metalloproteinase (MMP)–9 plays a central role in tumor progression and metastasis by stimulating cell migration, tumor invasion, and angiogenesis. To gain insights into MMP-9 expression, we investigated its epigenetic control in a reversible model of cancer that is initiated by infection with intracellular Theileria parasites. Gene induction by parasite infection was associated with trimethylation of histone H3K4 (H3K4me3) at the MMP-9 promoter. Notably, we found that the H3K4 methyltransferase SMYD3 was the only histone methyltransferase upregulated upon infection. SMYD3 is overexpressed in many types of cancer cells, but its contributions to malignant pathophysiology are unclear. We found that overexpression of SMYD3 was sufficient to induce MMP-9 expression in transformed leukocytes and fibrosarcoma cells and that proinflammatory phorbol esters further enhanced this effect. Furthermore, SMYD3 was sufficient to increase cell migration associated with MMP-9 expression. In contrast, RNA interference–mediated knockdown of SMYD3 decreased H3K4me3 modification of the MMP-9 promoter, reduced MMP-9 expression, and reduced tumor cell proliferation. Furthermore, SMYD3 knockdown also reduced cellular invasion in a zebrafish xenograft model of cancer. Together, our results define SMYD3 as an important new regulator of MMP-9 transcription, and they provide a molecular link between SMYD3 overexpression and metastatic cancer progression. Cancer Res; 72(3); 810–20. ©2011 AACR.
Metastatic Cells Can Escape the Proapoptotic Effects of TNF-α through Increased Autocrine IL-6/STAT3 Signaling
Authors: Li Shun , Wang Ni , Brodt Pnina
Published: December 2011

The liver is a common site for cancer metastases in which the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the proapoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a proinflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacities of poorly metastatic cells in the liver. Mechanistic investigations in vitro revealed that IGF-IR overexpression increased cell survival in the presence of high levels of TNF-α, in a manner associated with increased autocrine production of interleukin-6 (IL)-6. In turn, tumor cell–derived IL-6 induced gp130 and IL-6R–dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. We found that IL-6 production and cell death resistance were dose dependent with increasing TNF-α levels. In addition, RNA interference–mediated knockdown of either IL-6 or gp130 that established a blockade to autocrine STAT3 induction was sufficient to abolish the prosurvival effect of TNF-α and to inhibit liver metastasis. Taken together, our findings define an IGF-IR–mediated mechanism of cancer cell survival that is critical for metastatic colonization of the liver. Cancer Res; 72(4); 865–75. ©2011 AACR.
A Novel FoxM1-Caveolin Signaling Pathway Promotes Pancreatic Cancer Invasion and Metastasis
Authors: Huang Chen , Qiu Zhengjun , Wang Liwei , Peng Zhihai , Jia Zhiliang , Logsdon Craig D. , Le Xiangdong , Wei Daoyan , Huang Suyun , Xie Keping
Published: December 2011

Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its precise functional roles and regulation remain unclear. In this study, we determined the oncogenic function of Cav-1 in preclinical models of pancreatic cancer and in human tissue specimens. Cav-1 expression levels correlated with metastatic potential and epithelial–mesenchymal transition (EMT) in both mouse and human pancreatic cancer cells. Elevated levels in cells promoted EMT, migration, invasion, and metastasis in animal models, whereas RNA interference (RNAi)-mediated knockdown inhibited these processes. We determined that levels of Cav-1 and the Forkhead transcription factor FoxM1 correlated directly in pancreatic cancer cells and tumor tissues. Enforced expression of FoxM1 increased Cav-1 levels, whereas RNAi-mediated knockdown of FoxM1 had the opposite effect. FoxM1 directly bound to the promoter region of Cav-1 gene and positively transactivated its activity. Collectively, our findings defined Cav-1 as an important downstream oncogenic target of FoxM1, suggesting that dysregulated signaling of this novel FoxM1-Cav-1 pathway promotes pancreatic cancer development and progression. Cancer Res; 72(3); 655–65. ©2011 AACR.
Urinary Red Blood Cells: Not Only Glomerular or Nonglomerular
Authors: Tesser Poloni José Antonio , Bosan Istifanus Bala , Garigali Giuseppe , Fogazzi Giovanni B.
Published: December 2011

Two main types of red blood cells, isomorphic and dysmorphic, are found in the urine sediment, indicating nonglomerular and glomerular hematuria, respectively. Occasionally, however, other types of red blood cells such as sickle cells, anisocytes, poikilocytes, elliptocytes and dacryocytes can be seen in the urine sediment of patients with hematuria. This paper describes such cases reported in the literature in which such unusual urinary red blood cells have been found and the experience of the authors on this subject.
p53, a Pivotal Effector of a Functional Cross-Talk Linking Presenilins and Pen-2
Authors: Checler F. , Dunys J.
Published: December 2011

The γ-secretase is a multiprotein complex responsible for the ultimate cut yielding amyloid-β peptides and their N-terminal truncated species. This complex is composed of at least four distinct entities, namely presenilin-1 (PS1) or PS2, anterior pharynx defective-1, presenilin enhancer-2 (Pen-2) and nicastrin. Very few studies examined the transcriptional regulation of this complex, and more precisely, whether some of the members functionally interact. Here, we summarize our previous data documenting the fact that Pen-2 controls cell death in a p53-dependent manner and our recent demonstration of a pivotal role of p53 as a regulator of Pen-2 transcription. As PS trigger amyloid precursor protein intracellular domain-dependent regulation of p53, our studies delineate a feedback control mechanism by which PS and Pen-2 functionally interact in a p53-dependent manner.
The Cytotoxic Effect of Combined Hyperthermia and Taxane Chemotherapy on Ovarian Cancer Cells: Results of an in vitro Study
Authors: Muller M. , Chérel M. , Dupré P.-F. , Gouard S. , Collet M. , Classe J.-M.
Published: December 2011

Purpose: Hyperthermic intraperitoneal chemotherapy (HIPEC) is under continuous evaluation as a potential treatment for ovarian cancer. The purpose of this study was to evaluate the effect of chemotherapy, drug concentration and temperature. Materials and Methods: We examined the combined effects of hyperthermia and taxane chemotherapy on the clonogenic survival of the human ovarian carcinoma SHIN-3 cell line in vitro. Results: When hyperthermia was combined with chemotherapy, the median lethal dose (LD50) was equivalent regardless of the duration of exposure, and was independent of the exposure temperature. Taxanes showed a similar LD50 over the temperature range tested. Conclusions: In our study, hyperthermia does not increase the cytotoxic effects of taxanes, at least for the concentrations and durations tested.
Doubly Committed Ventricular Septal Defect: Single-Centre Experience and Midterm Follow-Up
Authors: Gabriels Charlien , Gewillig Marc , Meyns Bart , Troost Els , Van De Bruaene Alexander , Van Damme Sara , Budts Werner
Published: December 2011

Background: Doubly committed ventricular septal defect (dcVSD) is the least common type of VSD. Because published studies are rather scarce, this study aimed at evaluating the midterm outcome of dcVSDs. Methods: The records of all patients registered in the database of Paediatric and Congenital Cardiology, University Hospitals Leuven, with a dcVSD at 16 years of age were reviewed. Clinical, electrocardiographic and transthoracic echocardiographic changes from baseline, defined as of the age of 16 years, until the latest follow-up were compared. Results: Thirty-three patients (20 males, median age 26 years, interquartile range 12) were followed for a median time of 7.9 years (interquartile range 9.8, time range 2–25.9). No deaths occurred. In 15 patients (45%), the defect remained patent at baseline. During follow-up, two spontaneous closures (13%) occurred. Eighteen patients (55%) required closure before the age of 16 years. Five (28%) needed reoperation. In the dcVSD closure group, left ventricular ejection fraction decreased from 69 ± 12 to 61 ± 6% (p = 0.028). No significant changes in pulmonary arterial hypertension were noticed. Conclusions: Patients with persistently patent dcVSD remained nearly event free during follow-up. Event-free survival after dcVSD closure was markedly lower. These patients developed reduced left ventricular function and had a high risk of reintervention.
Survival after Starting Renal Replacement Treatment in Patients with Autosomal Dominant Polycystic Kidney Disease: A Single-Centre 40-Year Study
Authors: Haynes Richard , Kheradmand Farhad , Winearls Christopher G.
Published: December 2011

Background/Aims: Adult polycystic kidney disease (ADPKD) has a predictable natural history and the relative lack of co-morbidity allows a relatively unconfounded assessment of survival. We examined whether survival on renal replacement treatment (RRT) has improved over the last four decades compared to that in the general population. Methods: We conducted a retrospective cohort study of all patients with ADPKD who received RRT between 1971 and 2000 at the Oxford Kidney Unit. The main exposure was period of start of treatment (1971–1985 vs. 1986–2000) and the key outcome was overall survival. Standard Cox regression techniques were used to assess the association between these baseline variables and survival. Results: Age at start of RRT (HR per 1 year 1.08; 95% CI 1.06–1.10) and presence of a functioning transplant (HR 0.22; 95% CI 0.16–0.31) were associated with improved survival in unadjusted analyses. After adjustment for age the period of treatment also became a significant predictor of overall survival (HR 0.67; 95% CI 0.47–0.97). Conclusions: Survival on RRT appears to have improved and exceeds that observed in the general population, such that RRT now provides almost two-thirds of the life expectancy of the general population, compared to about half in earlier decades.
Phosphorylation of ERK1/2 in Dorsal Root Ganglia following Sequential Mustard Oil and Thermal Stimulation of the Rat Hind Paw
Authors: Donnerer Josef , Liebmann Ingrid
Published: December 2011

The effect of a sequential stimulation by mustard oil and noxious heat or cold on the phosphorylation of ERK1/2 in sensory afferents was investigated. The stimuli were applied to the rat hind paw and phospho-ERK1/2 (p-ERK1/2) was measured by fluorescence-immunohistochemistry in the lumbar dorsal root ganglia (DRGs) neurons. All stimuli lead to a significant increase in the number of small size DRG cells displaying cytoplasmic staining for p-ERK1/2. The combination of mustard oil with cold significantly increased the number of cells with cytoplasmic staining above the level obtained with cold stimulus alone, however this was not observed with the combination of mustard oil and heat. Nuclear staining was weak and was found increased by mustard oil combined with cold stimulation. Mustard oil is known to activate TRPA1 and TRPV1 channels, heat TRPV1, and cold TRPA1 and TRPM8. The present findings shed new light on the DRG cell populations reacting with cytoplasmic and nuclear staining for p-ERK1/2 following sequential irritant chemical and thermal stimuli to the skin.
Short Telomere Length, Myocardial Infarction, Ischemic Heart Disease, and Early Death
Authors: Weischer Maren , Bojesen Stig E. , Cawthon Richard M. , Freiberg Jacob J. , Tybjærg-Hansen Anne , Nordestgaard Børge G.
Published: December 2011

Objective—

We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death.

Methods and Results—

We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies (
P
=7×10
−74
to
P
=3×10
−125
). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01–1.19) for myocardial infarction, 1.06 (1.00–1.11) for ischemic heart disease, and 1.09 (1.05–1.13) for early death per 1000–base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07–2.07) for myocardial infarction, 1.24 (1.01–1.53) for ischemic heart disease, and 1.25 (1.07–1.46) for early death.

Conclusion—

Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.
Disparity in Left Ventricular Stimulation Among Different Pacing Configurations in Cardiac Resynchronization Therapy
Authors: Huizar Jose F. , Kaszala Karoly , Koneru Jayanthi , Kowalski Marcin , Thacker Leroy R. , Wood Mark A. , Ellenbogen Kenneth A.
Published: December 2011

Background—

Cardiac resynchronization therapy (CRT) demands high energy utilization due to continuous biventricular pacing. Current technology allows 6 pacing configurations for a bipolar left ventricular (LV) lead. Understanding the energy requirements for each configuration will allow optimization of pacing output.

Methods and Results—

Pacing impedance, LV voltage threshold at 1.5 ms (rheobase) and 0.4 ms and chronaxie were obtained in 6 LV configurations in 49 consecutive patients undergoing CRT implantation or replacement. Strength-duration curves were derived using the Lapicque formula. Pacing impedances and voltage thresholds at 1.5 and 0.4 ms, calculated minimum threshold energy at chronaxie, current drain, energy thresholds at 0.4 ms, and strength-duration curves were statistically different between LV configurations (
P
<0.05). The lowest threshold energy requirements were found in Tip→right ventricular (RV) coil and Tip→Can configuration. Energy strength-duration curves involving the ring as the cathode (Ring→RV, Ring→Can, and Ring→Tip) had the highest LV thresholds. The pacing configuration with the lowest energy threshold correlated 89% of the time with the lowest voltage threshold at 0.4 ms. The probability to reach LV thresholds <1.5 V at 0.4 ms was increased from 51% with 2 LV configurations to 67% with 6 LV configurations.

Conclusions—

Pacing impedance, LV thresholds, minimum threshold energy at chronaxie, current drain, voltage, and energy strength-duration curves were statistically different between LV pacing configurations. LV pacing configuration with the lowest voltage threshold does not always reflects the lowest energy threshold, particularly in the presence of a low impedance configuration. The availability of 6 LV configurations increases the probability of optimizing LV pacing output.