bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise-rest cycles do not alter local and whole body heat loss responses
Authors: Gagnon Daniel , Kenny Glen P.
Published: January 2011

Previous studies have suggested that greater core temperatures during intermittent exercise (Ex) are due to attenuated sweating [upper back sweat rate (SR)] and skin blood flow (SkBF) responses. We evaluated the hypothesis that heat loss is not altered during exercise-rest cycles (ER). Ten male participants randomly performed four 120-min trials: 1) 60-min Ex and 60-min recovery (60ER); 2) 3 × 20-min Ex separated by 20-min recoveries (20ER); 3) 6 × 10-min Ex separated by 10-min recoveries (10ER), or 4) 12 × 5-min Ex separated by 5-min recoveries (5ER). Exercise was performed at a workload of 130 W at 35°C. Whole body heat exchange was determined by direct calorimetry. Core temperature, SR (by ventilated capsule), and SkBF (by laser-doppler) were measured continuously. Evaporative heat loss (EHL) progressively increased with each ER, such that it was significantly greater ( P ≤ 0.05) at the end of the last compared with the first Ex for 5ER (299 ± 39 vs. 440 ± 41 W), 10ER (425 ± 51 vs. 519 ± 45 W), and 20ER (515 ± 63 vs. 575 ± 74 W). The slope of the EHL response against esophageal temperature significantly increased from the first to the last Ex within the 10ER (376 ± 56 vs. 445 ± 89 W/°C, P ≤ 0.05) and 20ER (535 ± 85 vs. 588 ± 28 W/°C, P ≤ 0.05) conditions, but not during 5ER (296 ± 96 W/°C vs. 278 ± 95 W/°C, P = 0.237). In contrast, the slope of the SkBF response against esophageal temperature did not significantly change from the first to the last Ex (5ER: 51 ± 23 vs. 54 ± 19%/°C, P = 0.848; 10ER: 53 ± 8 vs. 56 ± 21%/°C, P = 0.786; 20ER: 44 ± 20 vs. 50 ± 27%/°C, P = 0.432). Overall, no differences in body heat content and core temperature were observed. These results suggest that altered local and whole body heat loss responses do not explain the previously observed greater core temperatures during intermittent exercise.
Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle
Authors: Rivas Donato A. , Lessard Sarah J. , Saito Misato , Friedhuber Anna M. , Koch Lauren G. , Britton Steven L. , Yaspelkis Ben B. , Hawley John A.
Published: January 2011

Chronic metabolic diseases develop from the complex interaction of environmental and genetic factors, although the extent to which each contributes to these disorders is unknown. Here, we test the hypothesis that artificial selection for low intrinsic aerobic running capacity is associated with reduced skeletal muscle metabolism and impaired metabolic health. Rat models for low- (LCR) and high- (HCR) intrinsic running capacity were derived from genetically heterogeneous N:NIH stock for 20 generations. Artificial selection produced a 530% difference in running capacity between LCR/HCR, which was associated with significant functional differences in glucose and lipid handling by skeletal muscle, as assessed by hindlimb perfusion. LCR had reduced rates of skeletal muscle glucose uptake (∼30%; P = 0.04), glucose oxidation (∼50%; P = 0.04), and lipid oxidation (∼40%; P = 0.02). Artificial selection for low aerobic capacity was also linked with reduced molecular signaling, decreased muscle glycogen, and triglyceride storage, and a lower mitochondrial content in skeletal muscle, with the most profound changes to these parameters evident in white rather than red muscle. We show that a low intrinsic aerobic running capacity confers reduced insulin sensitivity in skeletal muscle and is associated with impaired markers of metabolic health compared with high intrinsic running capacity. Furthermore, selection for high running capacity, in the absence of exercise training, endows increased skeletal muscle insulin sensitivity and oxidative capacity in specifically white muscle rather than red muscle. These data provide evidence that differences in white muscle may have a role in the divergent aerobic capacity observed in this generation of LCR/HCR.
Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)
Authors: Belibi Franck , Zafar Iram , Ravichandran Kameswaran , Segvic Anamarija Bauer , Jani Alkesh , Ljubanovic Danica Galesic , Edelstein Charles L.
Published: January 2011

Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1α (HIF-1α). HIF-1α and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1α expression and autophagy in rat and mouse models of PKD. HIF-1α was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/− mice with a mutation in the Pkd2 gene were studied. HIF-1α was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/− kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1α. To determine the role of HIF-1α in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1α inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1α is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1α did not have a therapeutic effect.
Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure
Authors: Polichnowski Aaron J. , Lu Limin , Cowley Allen W.
Published: January 2011

The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng·kg−1·min−1)+ Nω-nitro-l-arginine methyl ester (l-NAME; 1.4 μg·kg−1·min−1) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo-controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 ± 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 ± 0.2 mmHg) kidneys and kidneys from sham rats (108.3 ± 0.1 mmHg). ANG II+l-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ∼3.5-fold increase in renal outer medullary tubular injury, ∼2-fold increase in outer medullary interstitial fibrosis, ∼2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations.
Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone
Authors: Wesson Donald E. , Simoni Jan , Broglio Kristine , Sheather Simon
Published: January 2011

Dietary alkali slows GFR decline in humans with a moderately reduced glomerular filtration rate (GFR) despite the absence of metabolic acidosis. Similarly, dietary alkali slows GFR decline in animals with 2/3 nephrectomy (Nx), a chronic kidney disease (CKD) model without metabolic acidosis in which GFR decline is mediated by acid (H+) retention through endothelin (ET) and mineralocorticoid receptors. To gain insight as to whether this mechanism might mediate GFR decline in humans, we explored whether macroalbuminuric subjects with moderately reduced (CKD stage 2 = 60–90 ml/min; CKD 2) compared with normal estimated GFR (>90 ml/min; CKD 1), each without metabolic acidosis, have H+retention that increases plasma levels of ET-1 and aldosterone. Baseline plasma ET and aldosterone concentrations were each higher in CKD 2 than CKD 1. Baseline dietary H+and urine net acid excretion (NAE) were not different between groups, but an acute oral NaHCO3bolus reduced urine NAE less (i.e., postbolus urine NAE was higher) in CKD 2 than CKD 1, consistent with greater H+retention in CKD 2 subjects. Thirty days of oral NaHCO3reduced H+retention in CKD 2 but not CKD 1 subjects and reduced plasma ET and aldosterone in both groups but to levels that remained higher in CKD 2 for each. Subjects with CKD stage 2 eGFR and no metabolic acidosis nevertheless have H+retention that increases plasma ET and aldosterone levels, factors that might mediate subsequent GFR decline and other untoward vascular effects.
Metabolomic response to exercise training in lean and diet-induced obese mice
Authors: Duggan Gavin E. , Hittel Dustin S. , Sensen Christoph W. , Weljie Aalim M. , Vogel Hans J. , Shearer Jane
Published: January 2011

Exercise training is a common therapeutic approach known to antagonize the metabolic consequences of obesity. The aims of the present study were to examine 1) whether short-term, moderate-intensity exercise training alters the basal metabolite profile and 2) if 10 days of mild exercise training can correct obesity-induced shifts in metabolic spectra. After being weaned, male C57BL/6J littermates were randomly divided into two diet groups: low fat (LF) or high fat (HF). After 12 wk of dietary manipulation, HF animals were obese and hyperglycemic compared with LF animals. Mice from each group were further divided into sedentary or exercise treatments. Exercise training consisted of wheel running exercise (2 h/day, 10 days, 5.64 m/min). After exercise training, animals were rested (36 h) and fasted (6 h) before serum collection. Samples were analyzed by high-resolution one-dimensional proton NMR. Fifty high- and medium-concentration metabolites were identified. Pattern recognition algorithms and multivariate modeling were used to identify and isolate significant metabolites changing in response to HF and exercise training. The results showed that while exercise can mitigate some of the abnormal patterns in metabolic spectra induced by HF diet feeding, they cannot negate it. In fact, when the effects of diet and exercise were compared, diet was a stronger predictor and had the larger influence on the metabolic profile. External validation of models showed that diet could be correctly classified with an accuracy of 89%, whereas exercise training could be classified 73% of the time. The results demonstrate metabolomics to effectively characterize obesity-induced perturbations in metabolism and support the concept that exercise is beneficial for this condition.
Physiological clustering of visual channels in the mouse retina
Authors: Farrow Karl , Masland Richard H.
Published: January 2011

Anatomy predicts that mammalian retinas should have in excess of 12 physiological channels, each encoding a specific aspect of the visual scene. Although several channels have been correlated with morphological cell types, the number of morphological types generally exceeds the known physiological types. Here, we attempted to sort the ganglion cells of the mouse retina purely on a physiological basis. The null hypothesis was that the outputs of the ganglion cells form a continuum or should be divided into only a few types. We recorded the spiking output of 471 retinal ganglion cells on a multielectrode array while presenting 4 classes of visual stimuli. Five parameters were chosen to describe each cell's response characteristics, including relative amplitude of the ON and OFF responses, response latency, response transience, direction selectivity, and the receptive field surround. We compared the results of four clustering routines and judged the results using the relevant validation indices. The optimal partition was the 12-cluster solution of the Fuzzy Gustafson-Kessel algorithm. This classification contained three visual channels that carried predominately OFF responses, six that carried ON responses, and three that carried both ON and OFF information. They differed in other parameters as well. Other evidence suggests that the true number of cell types in the mouse retina may be somewhat larger than 12, and a definitive typology will probably require broader stimulus sets and characterization of more response parameters. Nonetheless, the present results do allow us to reject the null hypothesis: it appears that in addition to well-known cell types (such as the ON-OFF direction selectivity cells) numerous other cell classes can be identified in the mouse retina based solely on their responses to a standard set of simple visual stimuli.
Direction and speed tuning to visual motion in cortical areas MT and MSTd during smooth pursuit eye movements
Authors: Inaba Naoko , Miura Kenichiro , Kawano Kenji
Published: January 2011

When tracking a moving target in the natural world with pursuit eye movement, our visual system must compensate for the self-induced retinal slip of the visual features in the background to enable us to perceive their actual motion. We previously reported that the speed of the background stimulus in space is represented by dorsal medial superior temporal (MSTd) neurons in the monkey cortex, which compensate for retinal image motion resulting from eye movements when the direction of the pursuit and background motion are parallel to the preferred direction of each neuron. To further characterize the compensation observed in the MSTd responses to the background motion, we recorded single unit activities in cortical areas middle temporal (MT) and MSTd, and we selected neurons responsive to a large-field visual stimulus. We studied their responses to the large-field stimulus in the background while monkeys pursued a moving target and while fixated a stationary target. We investigated whether compensation for retinal image motion of the background depended on the speed of pursuit. We also asked whether the directional selectivity of each neuron in relation to the external world remained the same even during pursuit and whether compensation for retinal image motion occurred irrespective of the direction of the pursuit. We found that the majority of the MSTd neurons responded to the visual motion in space by compensating for the image motion on the retina resulting from the pursuit regardless of pursuit speed and direction, whereas most of the MT neurons responded in relation to the genuine retinal image motion.
The motor system plays the violin: a musical metaphor inferred from the oscillatory activity of the α-motoneuron pools during locomotion
Authors: Chiovetto Enrico
Published: January 2011

Despite substantial advances in the field, particularly resulting from physiological studies in animals, the neural mechanisms underlying the generation of many motor behaviors in humans remain unclear. A recent study (Cappellini G et al. J Neurophysiol 104: 3064–3073, 2010) sheds more light on this topic. Like the string of a violin, the α-motoneuron pools in the spinal cord during locomotion show continuous and oscillatory patterns of activation. In this report, the implications and relevance of this finding are discussed in a general framework that includes neurophysiology, optimal control theory, and robotics.
SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts
Authors: Wang Hong-Sheng , Arvanitis Demetrios A. , Dong Min , Niklewski Paul J. , Zhao Wen , Lam Chi Keung , Kranias Evangelia G. , Sanoudou Despina
Published: January 2011

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), is a key regulator of myocyte Ca2+cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca2+cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na+and K+homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca2+current, Na+/Ca2+exchanger, transient outward K+current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca2+load and overall Ca2+dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.
Similarities and Differences in the Glycosylation Mechanisms in Prokaryotes and Eukaryotes
Authors: Dell Anne , Galadari Alaa , Sastre Federico , Hitchen Paul
Published: January 2011

Recent years have witnessed a rapid growth in the number and diversity of prokaryotic proteins shown to carry N- and/or O-glycans, with protein glycosylation now considered as fundamental to the biology of these organisms as it is in eukaryotic systems. This article overviews the major glycosylation pathways that are known to exist in eukarya, bacteria and archaea. These are (i) oligosaccharyltransferase (OST)-mediated N-glycosylation which is abundant in eukarya and archaea, but is restricted to a limited range of bacteria; (ii) stepwise cytoplasmic N-glycosylation that has so far only been confirmed in the bacterial domain; (iii) OST-mediated O-glycosylation which appears to be characteristic of bacteria; and (iv) stepwise O-glycosylation which is common in eukarya and bacteria. A key aim of the review is to integrate information from the three domains of life in order to highlight commonalities in glycosylation processes. We show how the OST-mediated N- and O-glycosylation pathways share cytoplasmic assembly of lipid-linked oligosaccharides, flipping across the ER/periplasmic/cytoplasmic membranes, and transferring “en bloc” to the protein acceptor. Moreover these hallmarks are mirrored in lipopolysaccharide biosynthesis. Like in eukaryotes, stepwise O-glycosylation occurs on diverse bacterial proteins including flagellins, adhesins, autotransporters and lipoproteins, with O-glycosylation chain extension often coupled with secretory mechanisms.
Note on Isomorphism Theorems of Hyperrings
Authors: Velrajan Muthusamy , Asokkumar Arjunan
Published: January 2011

There are different notions of hyperrings (R, +, ·). In this paper, we
extend the isomorphism theorems to hyperrings, where the additions and the multiplications
are hyperoperations.
Permanence and Extinction of a Generalized Gause‐Type Predator‐Prey System with Periodic Coefficients
Authors: Luo Jinhuo
Published: January 2011

We study the permanence and extinction of a generalized Gause‐type predator‐prey system with periodic coefficients. We provide a sufficient and necessary condition to guarantee the predator and prey species to be permanent and a sufficient condition for the existence of a periodic solution. In addition we prove that when the predator population tends to extinction, the prey population keeps oscillating above a positive population level.
On a Maximal Number of Period Annuli
Authors: Kozmina Yelena , Sadyrbaev Felix
Published: January 2011

We consider equation x′′ + g(x) = 0, where g(x) is a polynomial,
allowing the equation to have multiple period annuli. We detect the
maximal number of possible period annuli for polynomials of odd degree and
show how the respective optimal polynomials can be constructed.
The Myocyte Expression of Adiponectin Receptors and PPARδ Is Highly Coordinated and Reflects Lipid Metabolism of the Human Donors
Authors: Ordelheide Anna-Maria , Heni Martin , Gommer Nadja , Gasse Lisa , Haas Carina , Guirguis Alke , Machicao Fausto , Häring Hans-Ulrich , Staiger Harald
Published: January 2011

Muscle lipid oxidation is stimulated by peroxisome proliferator-activated receptor (PPAR) δ or adiponectin receptor signalling. We studied human myocyte expression of the PPARδ and adiponectin receptor genes and their relationship to lipid parameters of the donors. The mRNA levels of the three adiponectin receptors, AdipoR1, AdipoR2, and T-cadherin, were highly interrelated (r≥0.91). However, they were not associated with GPBAR1, an unrelated membrane receptor. In addition, the adiponectin receptors were positively associated with PPARδ expression (r≥0.75). However, they were not associated with PPARα. Using stepwise multiple linear regression analysis, PPARδ was a significant determinant of T-cadherin (P=.0002). However, pharmacological PPARδ activation did not increase T-cadherin expression. The myocyte expression levels of AdipoR1 and T-cadherin were inversely associated with the donors' fasting plasma triglycerides (P<.03). In conclusion, myocyte expression of PPARδ and the adiponectin receptors are highly coordinated, and this might be of relevance for human lipid metabolism in vivo.
First Integrals for Two Linearly Coupled Nonlinear Duffing Oscillators
Authors: Naz R. , Naeem I. , Mahomed F. M.
Published: January 2011

We investigate Noether and partial Noether operators of point type corresponding to a Lagrangian and a partial Lagrangian for a system of two linearly coupled
nonlinear Duffing oscillators. Then, the first integrals with respect to Noether
and partial Noether operators of point type are obtained explicitly by utilizing Noether and partial Noether theorems for the system under consideration.
Moreover, if the partial Euler‐Lagrange equations are independent of derivatives, then the partial Noether operators become Noether point symmetry generators
for such equations. The difference arises in the gauge terms due to Lagrangians
being different for respective approaches. This study points to new ways of constructing first integrals for nonlinear equations without regard to a Lagrangian.
We have illustrated it here for nonlinear Duffing oscillators.
hPuf-A/KIAA0020 Modulates PARP-1 Cleavage upon Genotoxic Stress
Authors: Chang Hao-Yen , Fan Chi-Chen , Chu Po-Chen , Hong Bo-En , Lee Hyeon Jeong , Chang Mau-Sun
Published: January 2011

Human hPuf-A/KIAA0020 was first identified as a new minor histocompatibility antigen in 2001. Its zebrafish orthologue contains six Pumilio-homology RNA-binding domains and has been shown to participate in the development of eyes and primordial germ cells, but the cellular function of hPuf-A remains unclear. In this report, we showed that hPuf-A predominantly localized in the nucleoli with minor punctate signals in the nucleoplasm. The nucleolar localization of hPuf-A would redistribute to the nucleoplasm after the treatment of RNA polymerase inhibitors (actinomycin D and 5,6-dichlorobenzimidazole riboside) and topoisomerase inhibitors [camptothecin (CPT) and etoposide]. Interestingly, knockdown of hPuf-A sensitized cells to CPT and UV treatment and cells constitutively overexpressing hPuf-A became more resistant to genotoxic exposure. Affinity gel pull-down coupled with mass spectrometric analysis identified PARP-1 as one of the hPuf-A interacting proteins. hPuf-A specifically interacts with the catalytic domain of PARP-1 and inhibits poly(ADP-ribosyl)ation of PARP-1 in vitro. Depletion of hPuf-A increased the cleaved PARP-1 and overexpression of hPuf-A lessened PARP-1 cleavage when cells were exposed to CPT and UV light. Collectively, hPuf-A may regulate cellular response to genotoxic stress by inhibiting PARP-1 activity and thus preventing PARP-1 degradation by caspase-3. Cancer Res; 71(3); 1126–34. ©2011 AACR.
Clinical Significance of Osteoprotegerin Expression in Human Colorectal Cancer
Authors: Tsukamoto Shunsuke , Ishikawa Toshiaki , Iida Satoru , Ishiguro Megumi , Mogushi Kaoru , Mizushima Hiroshi , Uetake Hiroyuki , Tanaka Hiroshi , Sugihara Kenichi
Published: January 2011

Purpose: This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC).

Experimental Design: The expression profiles of cancer cells in 104 patients with CRC were examined using laser microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells, especially in patients with distant metastases, was a prerequisite to select candidate genes. The mRNA expression of candidate genes was investigated by quantitative reverse transcriptase PCR (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study and investigated the relationship between protein expression and clinicopathologic features in 274 CRC patients.

Results: Using microarray analysis, we identified 6 candidate genes related to distant metastases in CRC patients. Among these genes, osteoprotegerin (OPG) is known to be associated with aggressiveness in several cancers through inhibition of apoptosis via neutralization of the function of TNF-related apoptosis-inducing ligand. The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastases than those without metastases. Overexpression of OPG protein was associated with significantly worse overall survival and relapse-free survival. Moreover, overexpression of the OPG protein was an independent risk factor for CRC recurrence.

Conclusion: Overexpression of OPG may be a predictive biomarker of CRC recurrence and a target for treatment of this disease. Clin Cancer Res; 17(8); 2444–50. ©2011 AACR.
The Atr Protein Kinase Controls UV-Dependent Upregulation of p16INK4A Through Inhibition of Skp2-Related Polyubiquitination/Degradation
Authors: Al-Khalaf Huda H. , Hendrayani Siti-Faujiah , Aboussekhra Abdelilah
Published: January 2011

The tumor suppressor p16INK4A, a phosphoprotein that exists in human cells under both phosphorylated and nonphosphorylated forms, plays crucial roles during the cellular response to UV light. However, it is still unclear how this protein is activated in response to this carcinogenic agent. We have shown here that UVC upregulates p16INK4A and the phosphorylated form of the protein at the 4 serine sites; Ser-7, Ser-8, Ser-140, and Ser-152. This accumulation of p16INK4A occurred through increasing the stability of both forms of the protein. Importantly, phospho-p16INK4A showed much higher stability, and UV treatment strongly increased its level in absence of de novo protein synthesis. Furthermore, we have shown that the UV-dependent upregulation of both forms of p16INK4A is under the control of the protein kinase Atr, which suppresses their UVC-dependent proteasomal degradation. Interestingly, although this degradation is ubiquitin-related for p16INK4A through the Skp2 ubiquitin ligase protein, it is ubiquitin-independent for the phosphorylated form. In addition, we present clear evidence that Skp2 is upregulated in ATR-deficient cells, leading to the downregulation of the p27Kip1 protein in response to UVC light. Moreover, we have shown a preferential association of endogeneous phospho-p16INK4A with Cdk4. This association increased following UV-treatment mainly for p16INK4A phosphorylated at Ser-140 and Ser-152. Besides, we have shown that Atr regulates UV-related p16/Cdk4-dependent and -independent phosphorylation of pRB and G1 cell cycle delay. Together, these results indicate that p16INK4A and p27Kip1 are key targets in the Atr-dependent signaling pathway in response to UV damage. Mol Cancer Res; 9(3); 311–9. ©2011 AACR.
Role of DNA Methylation in the Development of Diffuse-Type Gastric Cancer
Authors: Yamamoto Eiichiro , Suzuki Hiromu , Takamaru Hiroyuki , Yamamoto Hiroyuki , Toyota Minoru , Shinomura Yasuhisa
Published: January 2011

Cancer cells exhibit two opposing methylation abnormalities: genome-wide hypomethylation and gene promoter hypermethylation. Downregulation of E-cadherin (CDH1) plays a key role in the development of diffuse-type gastric cancer, and DNA methylation is a major cause of the gene’s silencing. Hereditary diffuse gastric cancer is caused by germline mutation of CDH1 gene, and DNA methylation frequently serves as the second hit completely inactivating the gene. In sporadic diffuse-type gastric cancer, methylation of CDH1 is more prevalent than mutation of the gene. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBV-associated GC) is characterized by concurrent methylation of multiple genes, and diffuse-type gastric cancer is frequently seen among EBV-associated GCs. Patients with pangastritis or enlarged-fold gastritis, which are both caused by Helicobacter pylori infection, reportedly have an increased risk for diffuse-type gastric cancer. Notably, the gastric mucosa of enlarged-fold gastritis patients exhibits CDH1 hypermethylation and genome-wide hypomethylation. These data suggest that aberrant DNA methylation is an essential promoter of carcinogenesis in individuals at high risk for diffuse-type gastric cancer.
Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency
Authors: Oelze Matthias , Knorr Maike , Schuhmacher Swenja , Heeren Tjebo , Otto Christian , Schulz Eberhard , Reifenberg Kurt , Wenzel Philip , Münzel Thomas , Daiber Andreas
Published: January 2011

Objective: In previous studies we and others have shown that streptozotocin (STZ)-induced diabetes in rats is associated with vascular oxidative stress and dysfunction. In the present study, we sought to determine whether vascular dysfunction and oxidative stress strictly depend on insulin deficiency. Methods: The effects of insulin (2.5 U/day s.c., 2 weeks) therapy on vascular disorders in STZ-induced (60 mg/kg i.v., 8 weeks) diabetes mellitus (type I) were studied in Wistar rats. The contribution of NADPH oxidase to overall oxidative stress was investigated by in vivo (30 mg/kg/day s.c., 4 days) and in vitro treatment with apocynin. Results: Insulin therapy completely normalized blood glucose, body weight, vascular dysfunction and oxidative stress as well as increased cardiac reactive oxygen and nitrogen species formation in diabetic rats, although diabetes was already established for 6 weeks before insulin therapy was started for the last 2 weeks of the total treatment interval. Apocynin normalized cardiac NADPH oxidase activity, and L-NAME effects suggest a role for uncoupled endothelial nitric oxide synthase in diabetic vascular complications. Conclusions: Our findings indicate that STZ-induced diabetes is a model of insulin-dependent diabetes (type 1) and that cardiovascular complications are probably not associated with systemic toxic side effects of STZ.
Endothelial Glycocalyx Structure in the Intact Carotid Artery: A Two-Photon Laser Scanning Microscopy Study
Authors: Reitsma Sietze , oude Egbrink Mirjam G.A. , Vink Hans , van den Berg Bernard M. , Lima Passos Valéria , Engels Wim , Slaaf Dick W. , van Zandvoort Marc A.M.J.
Published: January 2011

Background: The endothelial glycocalyx (EG) is the carbohydrate-rich luminal lining of endothelial cells that mediates permeability and blood cell-vessel wall interactions. To establish an atheroprotective role of the EG, adequate imaging and quantification of its properties in intact, viable, atherogenesis-prone arteries is needed. Methods: Carotid arteries of C57Bl6/J mice (n = 22) were isolated including the bifurcation, mounted in a perfusion chamber, and perfused with fluorescent lectin wheat germ agglutinin-fluorescein isothiocyanate. The EG was visualized through the vessel wall using two-photon laser scanning microscopy. An image quantification protocol was developed to assess EG thickness, which was sensitive to hyaluronidase-induced changes. Results: In the lesion-protected common carotid artery, EG thickness was found to be 2.3 ± 0.1 µm (mean ± SEM), while the surface area devoid of (wheat germ agglutinin-sensitive) EG was 8.9 ± 4.2%. Data from the external carotid artery were similar (2.5 ± 0.1 µm; 9.1 ± 5.0%). In the atherogenesis-prone internal carotid artery the EG-devoid surface area was significantly higher (27.4 ± 5.5%, p < 0.05); thickness at the remaining areas was 2.5 ± 0.1 µm. Conclusion: The EG can be adequately imaged and quantified using two-photon laser scanning microscopy in intact, viable mounted carotid arteries. Spatial EG differences could underlie atherogenesis.
Circulating Endothelial Cell Protein C Receptor: Endothelial Regulation and Cumulative Impact of Gender and A3 Haplotype
Authors: Guitton Christophe , Gérard Nathalie , Quillard Thibaut , Charreau Béatrice
Published: January 2011

Background: The endothelial cell (EC) protein C receptor (EPCR) negatively regulates coagulation and inflammation. Factors and mechanisms regulating the expression of cell-bound EPCR and the release of soluble (s) EPCR are still unclear. Methods: We investigated the reciprocal regulation of membrane-bound and sEPCR upon inflammation using primary cultures of vascular EC. The impact of 2 parameters, gender and EPCR gene A3 haplotype, on sEPCR plasma basal level and endothelial expression was examined by Elisa and flow cytometry. Results: Exposure of EC to tumor necrosis factor α causes a rapid downregulation of membrane-associated EPCR expression without affecting markedly the spontaneous release of sEPCR by EC. In a cohort of 100 healthy donors, we show that males express significantly higher basal sEPCR in plasma than females (194 ± 12 vs. 145 ± 9 ng/ml, respectively, p < 0.01). Both gender and EPCR A3 haplotype affect sEPCR plasma levels but have no apparent effect on EPCR expression by EC. No quantitative correlation between cellular expression and circulating blood sEPCR was observed, suggesting that endothelial expression may not reflect the plasma level. Conclusion: Male gender is another parameter with A3 haplotype associated with elevated sEPCR levels in blood, and both parameters may contribute to selective regulatory mechanisms of EPCR release upon inflammation.
Complications of Pediatric Auditory Brain Stem Implantation via Retrosigmoid Approach
Authors: Bayazit Yildirim A. , Abaday Ayça , Dogulu Fikret , Göksu Nebil
Published: January 2011

Objective: We aimed to present the complications of auditory brain stem implantations (ABI) in pediatric patients which were performed via retrosigmoid approach. Methods: Between March 2007 and February 2010, five prelingually deaf children underwent ABI (Medel device) operation via retrosigmoid approach. All children had severe cochlear malformations. The ages ranged from 20 months to 5 years. The perioperative complications encountered in 2 patients were evaluated retrospectively. Results: No intraoperative complication was observed in the patients. Cerebrospinal fluid (CSF) leakage was the most common postoperative complication that was seen in 2 patients. The CSF leak triggered a cascade of comorbidities, and elongated the hospitalization. Conclusion: Pediatric ABI surgery can lead to morbidity. The CSF leak is the most common complication encountered in retrosigmoid approach. The other complications usually result from long-term hospital stay during treatment period of the CSF leak. Therefore, every attempt must be made to prevent occurrence of CSF leaks in pediatric ABI operations.
Changes in Vascular Risk Factors from Midlife to Late Life and White Matter Lesions: A 20-Year Follow-Up Study
Authors: Vuorinen Miika , Solomon Alina , Rovio Suvi , Nieminen Lasse , Kåreholt Ingemar , Tuomilehto Jaakko , Soininen Hilkka , Kivipelto Miia
Published: January 2011

Background/Aims: This study investigated the relation of midlife blood pressure, total cholesterol, body mass index (BMI), their changes over time, apolipoprotein E, and white matter lesions (WML). Methods: Participants of the Cardiovascular Risk Factors, Aging and Incidence of Dementia study were derived from random, population-based samples previously surveyed in 1972, 1977, 1982 or 1987. In 1998, 1,449 (73%) individuals aged 65–79 years were re-examined (average follow-up 21 years). A subpopulation (n = 112) was scanned with a 1.5-tesla MRI scanner in 1998, and WML were assessed from fluid-attenuated inversion recovery images using a semi-quantitative visual rating scale. Results: Risk of late-life WML was related to midlife overweight (relative risk = 2.53; 95% CI = 1.70–2.89), obesity (2.94; 2.44–3.03), and hypertension (2.73; 1.81–3.08), even after adjustments for several confounding factors. Elevated BMI (>25) (2.26; 1.42–2.62) and hypertension (3.14; 1.83–3.40) from midlife to late life also increased the risk of WML. In addition, an association with WML was seen for decreasing blood pressure (hypertension at midlife but not at late life) (3.25; 2.46–3.41), even after controlling for antihypertensive treatment. Lipid-lowering drugs had a protective effect against WML (0.13; 0.02–0.59). Conclusions: These results indicate that early and sustained vascular risk factor control is associated with a lower likelihood of having more severe WML in late life.
Long-Term Outcomes of Combined Epicardial and Endocardial Ablation of Monomorphic Ventricular Tachycardia Related to Hypertrophic Cardiomyopathy
Authors: Dukkipati Srinivas R. , d'Avila Andre , Soejima Kyoko , Bala Rupa , Inada Keiichi , Singh Sheldon , Stevenson William G. , Marchlinski Francis E. , Reddy Vivek Y.
Published: January 2011

Background—

Monomorphic ventricular tachycardia (MMVT) is rare in patients with hypertrophic cardiomyopathy (HCM). There are limited data on the utility of catheter ablation for the treatment of MMVT in this population. This study details a series of case reports from multiple centers where combined epicardial-endocardial ablation was performed in a highly selected group of patients with HCM-related MMVT.

Methods and Results—

The cohort consisted of 10 patients with HCM-related MMVT. Pericardial access was achieved using the percutaneous subxyphoid approach. Epicardial and endocardial ventricular 3D bipolar voltage maps were generated. Ablation sites were identified using a combination of entrainment, activation, late/fractionated potential, and pace mapping. Electrophysiological-identified epicardial scar was present in 8 (80%) patients, endocardial scar in 6 (60%), and no scar in 1 (10%). In the 5 patients with inducible, stable MMVT, 3 cases were successfully terminated with ablation from the epicardium and 1 from the endocardium. The case that failed catheter ablation required surgical cryoablation to abolish the incessant VT. In the remaining 5 patients, 4 underwent epicardial and endocardial ablation of sites with good pace maps and late/fractionated potentials. No ablation was performed in the remaining patient because of noninducibility and lack of identifiable scar. After 37±17 months (limits, 2 to 62 months; median, 37 months), the freedom from recurrent implantable cardioverter-defibrillator shocks was 78% (7/9 patients) in those who underwent ablation.

Conclusions—

In highly selected patients with HCM, combined epicardial and endocardial mapping and ablation is a feasible and reasonably efficacious option for MMVT if refractory to aggressive trials of antiarrhythmic drugs and antitachycardia pacing.
Inhibition of Cardiac Ca
2+
Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Hwang Hyun Seok , Hasdemir Can , Laver Derek , Mehra Divya , Turhan Kutsal , Faggioni Michela , Yin Huiyong , Knollmann Björn C.
Published: January 2011

Background—

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.

Methods and Results—

We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2
−/−
myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca
2+
waves at clinically relevant concentrations, whereas Na
+
channel inhibitors without RyR2 blocking properties did not. In Casq2
−/−
mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice,
P
<0.05). QRS duration was not significantly different, indicating a similar degree of Na
+
channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.

Conclusions—

RyR2 cardiac Ca
2+
release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2
−/−
mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.
Percutaneous Transhepatic Venous Access for Catheter Ablation Procedures in Patients With Interruption of the Inferior Vena Cava
Authors: Singh Sheldon M. , Neuzil Petr , Skoka Jan , Kriz Radko , Popelova Jana , Love Barry A. , Mittnacht Alexander J.C. , Reddy Vivek Y.
Published: January 2011

Background—

Catheter ablation of left-sided atrial arrhythmias generally is performed using a transfemoral venous approach through the inferior vena cava (IVC). In this report, we assessed the feasibility of a percutaneous transhepatic approach to ablation of left-sided atrial arrhythmias in 2 patients with interruption of the IVC.

Methods and Results—

Patient 1 had atrial flutter in the setting of complex congenital heart disease and prior Fontan for univentricular physiology and a single atrium. Patient 2 had atrial fibrillation. Percutaneous hepatic vein access was obtained with ultrasound and fluoroscopic guidance. Transseptal catheterization was performed in patient 2. After the procedure, the hepatic tract in patient 1 was cauterized using a bipolar radiofrequency catheter, and an Amplatzer vascular plug was used in patient 2 to obtain hemostasis. Percutaneous hepatic vein access was achieved without complications. After electroanatomical mapping, a linear lesion was placed between the single atrioventricular valve and the confluence of the hepatic veins in patient 1; this terminated the flutter, and bidirectional block was achieved. In patient 2, the pulmonary veins were electrically isolated using an extraostial approach, isolating the ipsilateral veins in pairs. Additionally, ablation of right-side atrial flutter was achieved by obtaining bidirectional block across a linear lesion between the tricuspid valve and confluence of the hepatic veins. Hemostasis of the transhepatic tract was attained in both patients.

Conclusions—

In patients with interrupted IVCs, a percutaneous transhepatic approach is a feasible alternative for performing catheter ablation of complex left-sided arrhythmias.
A New Parametric Model of Vortex Tangential-Wind Profiles: Development, Testing, and Verification
Authors: Wood Vincent T. , White Luther W.
Published: January 2011

A new parametric model of vortex tangential-wind profiles is presented that is primarily designed to depict realistic-looking tangential wind profiles such as those in intense atmospheric vortices arising in dust devils, waterspouts, tornadoes, mesocyclones, and tropical cyclones. The profile employs five key parameters: maximum tangential wind, radius of maximum tangential wind, and three power-law exponents that shape different portions of the velocity profile. In particular, a new parameter is included controlling the broadly or sharply peaked profile in the annular zone of tangential velocity maximum. Different combinations of varying the model parameters are considered to investigate and understand their effects on the physical behaviors of tangential wind and corresponding vertical vorticity profiles. Additionally, the parametric tangential velocity and vorticity profiles are favorably compared to those of an idealized Rankine model and also those of a theoretical stagnant core vortex model in which no tangential velocity exists within a core boundary and a potential flow occurs outside the core. Furthermore, the parametric profiles are evaluated against and compared to those of two other idealized vortex models (Burgers–Rott and Sullivan). The comparative profiles indicate very good agreements with low root-mean-square errors of a few tenths of a meter per second and high correlation coefficients of nearly one. Thus, the veracity of the parametric model is demonstrated.
On the Structure and Teleconnections of North Atlantic Decadal Variability
Authors: Álvarez-García Francisco J. , OrtizBevia María J. , CabosNarvaez William D.
Published: January 2011

Decadal variability in the North Atlantic has been associated in the literature with a tripolar pattern of sea surface temperature (SST) anomalies that show one sign in the western midlatitudinal North Atlantic and the opposite in the subpolar and tropical North Atlantic. The present analysis of observed SST from 1870 to 2009 leads to the dissection of the SST tripole into two components, each with a different time scale in the decadal band and different teleconnections in the Atlantic basin; while the subpolar and tropical poles present quasi-decadal variations with a period of about 9 years, essentially uncorrelated with other parts of the basin, the center of action in the western midlatitudes is characterized by a longer time scale of about 14 years and significant correlations with the tropical South Atlantic and the Norwegian and North Sea(s). The 9-yr period variations are associated with an atmospheric configuration resembling the east Atlantic pattern, whereas the 14-yr period fluctuations seem to be related to the North Atlantic Oscillation pattern. Each component also bears a different relationship with the decadal variability in the Pacific Ocean.
Trends in the Frequency of Intense Precipitation Events in Southern and Southeastern Brazil during 1960–2004
Authors: Teixeira Mateus da Silva , Satyamurty Prakki
Published: January 2011

A new approach to define heavy and extreme rainfall events based on cluster analysis and area-average rainfall series is presented. The annual frequency of the heavy and extreme rainfall events is obtained for the southeastern and southern Brazil regions. In the 1960–2004 period, 510 (98) and 466 (77) heavy (extreme) rainfall events are identified in the two regions. Monthly distributions of the events closely follow the monthly climatological rainfall in the two regions. In both regions, annual heavy and extreme rainfall event frequencies present increasing trends in the 45-yr period. However, only in southern Brazil is the trend statistically significant. Although longer time series are necessary to ensure the existence of long-term trends, the positive trends are somewhat alarming since they indicate that climate changes, in terms of rainfall regimes, are possibly under way in Brazil.