bluuebunny/crossref_metadata_2025 huggingface dataset:
EXISTENCE AND UNIQUENESS OF A GLOBAL-IN-TIME SOLUTION TO A PHASE SEGREGATION PROBLEM OF THE ALLEN–CAHN TYPE
Authors: COLLI PIERLUIGI , GILARDI GIANNI , PODIO-GUIDUGLI PAOLO , SPREKELS JÜRGEN
Published: February 2010

We study a model of phase segregation of the Allen–Cahn type, consisting in a system of two differential equations, one partial and the other ordinary, respectively interpreted as balances of microforces and microenergy; the two unknowns are the order parameter entering the standard A–C equation and the chemical potential. We introduce a notion of maximal solution to the o.d.e., parametrized on the order-parameter field; and, by substitution in the p.d.e. of the so-obtained chemical potential field, we give the latter equation the form of an Allen–Cahn equation for the order parameter, with a memory term. Finally, we prove the existence and uniqueness of global-in-time smooth solutions to this modified A–C equation, and we give a description of the relative ω-limit set.
PARABOLIC AND DEGENERATE PARABOLIC MODELS FOR PRESSURE-DRIVEN TRANSPORT PROBLEMS
Authors: CHOQUET CATHERINE
Published: February 2010

We consider two models of flow and transport in porous media, the first one for consolidational flow in compressible sedimentary basins, the second one for flow in partially saturated media. Despite the differences in these physical settings, they lead to quite similar mathematical models with a strong pressure coupling. The first model is a coupled system of pde's of parabolic type. The second one involves a coupled system of pdes of degenerate parabolic–hyperbolic type. We state an existence result of weak solutions for both models.
ON RANDOM TOPOLOGICAL MARKOV CHAINS WITH BIG IMAGES AND PREIMAGES
Authors: STADLBAUER MANUEL
Published: February 2010

We introduce a relative notion of the "big images and preimages"-property for random topological Markov chains. This condition then implies that a relative version of the Ruelle–Perron–Frobenius theorem holds with respect to summable and locally Hölder continuous potentials.
A STUDY OF A CLASS OF NONLINEAR STOCHASTIC DELAY DIFFERENTIAL EQUATIONS
Authors: WU FUKE , HU SHIGENG
Published: February 2010

This paper establishes the existence-and-uniqueness theorems of the global solution to a class of stochastic delay differential equations only with the local Lipschitz condition but does not consider the linear growth condition and studies stochastic ultimate boundedness and the moment average in time. Here we allow the coefficients of these equations to be polynomial or their growths are controlled by polynomial speed. To illustrate our idea clearly, we consider a scalar equation and a special n-dimensional equation carefully.
C1 ROBUSTLY MINIMAL ITERATED FUNCTION SYSTEMS
Authors: GHANE F. H. , HOMBURG A. J. , SARIZADEH A.
Published: February 2010

We construct iterated function systems on compact manifolds that are C1 robustly minimal. On the m-dimensional torus and on two-dimensional compact manifolds, examples are provided of C1 robustly minimal iterated function systems that are generated by just two diffeomorphisms.
Silencing of Mustn1 inhibits myogenic fusion and differentiation
Authors: Liu Cheng , Gersch Robert P. , Hawke Thomas J. , Hadjiargyrou Michael
Published: February 2010

Mustn1 (Mustang, musculoskeletal temporally activated novel gene) was originally identified in fracture callus tissue, but its greatest expression is detected in skeletal muscle. Thus, we conducted experiments to investigate the expression and function of Mustn1 during myogenesis. Temporally, quantitative real-time PCR analysis of muscle samples from embryonic day 17 to 12 mo of age reveals that Mustn1 mRNA expression is greatest at 3 mo of age and beyond, consistent with the expression pattern of Myod. In situ hybridization shows abundant Mustn1 expression in somites and developing skeletal muscles, while in adult muscle, Mustn1 is localized to some peripherally located nuclei. Using RNA interference (RNAi), we investigated the function of Mustn1 in C2C12 myoblasts. Though silencing Mustn1 mRNA had no effect on myoblast proliferation, it did significantly impair myoblast differentiation, preventing myofusion. Specifically, when placed in low-serum medium for up to 6 days, Mustn1-silenced myoblasts elongated poorly and were mononucleated. In contrast, control RNAi-treated and parental myoblasts presented as large, multinucleated myotubes. Further supporting the morphological observations, immunocytochemistry of Mustn1-silenced cells demonstrated significant reductions in myogenin (Myog) and myosin heavy chain (Myhc) expression at 4 and 6 days of differentiation as compared with control and parental cells. The decreases in Myog and Myhc protein expression in Mustn1-silenced cells were associated with robust (∼3-fold or greater) decreases in the expression of Myod and desmin ( Des), as well as the myofusion markers calpain 1 ( Capn1), caveolin 3 ( Cav3), and cadherin 15 (M-cadherin; Cadh15). Overall, we demonstrate that Mustn1 is an essential regulator of myogenic differentiation and myofusion, and our findings implicate Myod and Myog as its downstream targets.
The O2cost of the tension-time integral in isolated single myocytes during fatigue
Authors: Hepple Russell T. , Howlett Richard A. , Kindig Casey A. , Stary Creed M. , Hogan Michael C.
Published: February 2010

One proposed explanation for the V̇o2slow component is that lower-threshold motor units may fatigue and develop little or no tension but continue to use O2, thereby resulting in a dissociation of cellular respiration from force generation. The present study used intact isolated single myocytes with differing fatigue resistance profiles to investigate the relationship between fatigue, tension development, and aerobic metabolism. Single Xenopus skeletal muscle myofibers were allocated to a fast-fatiguing (FF) or a slow-fatiguing (SF) group, based on the contraction frequency required to elicit a fall in tension to 60% of peak. Phosphorescence quenching of a porphyrin compound was used to determine Δ intracellular Po2(PiO2; a proxy for V̇o2), and developed isometric tension was monitored to allow calculation of the time-integrated tension (TxT). Although peak ΔPiO2was not different between groups ( P = 0.36), peak tension was lower ( P < 0.05) in SF vs. FF (1.97 ± 0. 17 V vs. 2. 73 ± 0.30 V, respectively) and time to 60% of peak tension was significantly longer in SF vs. FF (242 ± 10 s vs. 203 ± 10 s, respectively). Before fatigue, both ΔPiO2and TxT rose proportionally with contraction frequency in SF and FF, resulting in ΔPiO2/TxT being identical between groups. At fatigue, TxT fell dramatically in both groups, but ΔPiO2decreased proportionately only in the FF group, resulting in an increase in ΔPiO2/TxT in the SF group relative to the prefatigue condition. These data show that more fatigue-resistant fibers maintain aerobic metabolism as they fatigue, resulting in an increased O2cost of contractions that could contribute to the V̇o2slow component seen in whole body exercise.
Serotonin neurons of the caudal raphe nuclei contribute to sympathetic recovery following hypotensive hemorrhage
Authors: Kung Ling-Hsuan , Glasgow Jaimee , Ruszaj Anna , Gray Thackery , Scrogin Karie E.
Published: February 2010

Serotonin is thought to contribute to the syncopal-like response that develops during severe blood loss by inhibiting presympathetic neurons of the rostroventrolateral medulla (RVLM). Here, we tested whether serotonin cells activated during hypotensive hemorrhage, i.e., express the protein product of the immediate early gene c-Fos, are critical for the normal sympathetic response to blood loss in unanesthetized rats. Serotonin-immunoreactive cells of the raphe obscurus and raphe magnus, parapyramidal cells of the B3 region, subependymal cells of the ventral parapyramidal region, and cells of the ventrolateral periaqueductal gray region were activated by hypotensive hemorrhage, but not by hypotension alone. In contrast to findings in anesthetized animals, lesion of hindbrain serotonergic cells sufficient to produce >80% loss of serotonin nerve terminal immunoreactivity in the RVLM accelerated the sympatholytic response to blood loss, attenuated recovery of sympathetic activity after termination of hemorrhage, and exaggerated metabolic acidosis. Hindbrain serotonin lesion also attenuated ventilatory and sympathetic responses to stimulation of central chemoreceptors but increased spontaneous arterial baroreflex sensitivity and decreased blood pressure variability. A more global neurotoxic lesion that also eliminated tryptophan hydroxylase-immunoreactive cells of the ventrolateral periaqueductal gray region had no further effect on the sympatholytic response to blood loss. Together, the data indicate that serotonin cells of the caudal hindbrain contribute to compensatory responses following blood loss that help maintain oxygenation of peripheral tissue in the unanesthetized rat. This effect may be related to facilitation of chemoreflex responses to acidosis.
Comparative analysis of nitrite uptake and hemoglobin-nitrite reactions in erythrocytes: sorting out uptake mechanisms and oxygenation dependencies
Authors: Jensen Frank B. , Rohde Sabina
Published: February 2010

Nitrite uptake into red blood cells (RBCs) precedes its intracellular reactions with hemoglobin (Hb) that forms nitric oxide (NO) during hypoxia. We investigated the uptake of nitrite and its reactions with Hb at different oxygen saturations (So2), using RBCs with (carp and rabbit) and without (hagfish and lamprey) anion exchanger-1 (AE1) in the membrane, with the aim to unravel the mechanisms and oxygenation dependencies of nitrite transport. Added nitrite rapidly diffused into the RBCs until equilibrium. The distribution ratio of nitrite across the membrane agreed with that expected from HNO2diffusion and AE1-mediated facilitated NO2−diffusion. Participation of HNO2diffusion was emphasized by rapid transmembrane nitrite equilibration also in the natural AE1 knockouts. Following the equilibration, nitrite was consumed by reacting with Hb, which created a continued inward diffusion controlled by intracellular reaction rates. Changes in nitrite uptake with So2, pH, or species were accordingly explained by corresponding changes in reaction rates. In carp, nitrite uptake rates increased linearly with decreasing So2over the entire So2range. In rabbit, nitrite uptake rates were highest at intermediate So2, producing a bell-shaped relationship with So2. Nitrite consumption increased ∼10-fold with a 1 unit decrease in pH, as expected from the involvement of protons in the reactions with Hb. The reaction of nitrite with deoxyhemoglobin was favored over that with oxyhemoglobin at intermediate So2. We propose a model for RBC nitrite uptake that involves both HNO2diffusion and AE1-mediated transport and that explains both the present and previous (sometimes puzzling) results.
Regulation of renal proximal tubule Na-K-ATPase by prostaglandins
Authors: Herman Maryann B. , Rajkhowa Trivikram , Cutuli Facundo , Springate James E. , Taub Mary
Published: February 2010

Prostaglandins (PGs) play a number of roles in the kidney, including regulation of salt and water reabsorption. In this report, evidence was obtained for stimulatory effects of PGs on Na-K-ATPase in primary cultures of rabbit renal proximal tubule (RPT) cells. The results of our real-time PCR studies indicate that in primary RPTs the effects of PGE2, the major renal PG, are mediated by four classes of PGE (EP) receptors. The role of these EP receptors in the regulation of Na-K-ATPase was examined at the transcriptional level. Na-K-ATPase consists of a catalytic α-subunit encoded by the ATP1A1 gene, as well as a β-subunit encoded by the ATP1B1 gene. Transient transfection studies conducted with pHβ1-1141 Luc, a human ATP1B1 promoter/luciferase construct, indicate that both PGE1and PGE2are stimulatory. The evidence for the involvement of both the cAMP and Ca2+signaling pathways includes the inhibitory effects of the myristolylated PKA inhibitor PKI, the adenylate cyclase (AC) inhibitor SQ22536, and the PKC inhibitors Gö 6976 and Ro-32-0432 on the PGE1stimulation. Other effectors that similarly act through cAMP and PKC were also stimulatory to transcription, including norepinephrine and dopamine. In addition to its effects on transcription, a chronic incubation with PGE1was observed to result in an increase in Na-K-ATPase mRNA levels as well as an increase in Na-K-ATPase activity. An acute stimulatory effect of PGE1on Na-K-ATPase was observed and was associated with an increase in the level of Na-K-ATPase in the basolateral membrane.
A high-fat diet increases risk of ventricular arrhythmia in female rats: enhanced arrhythmic risk in the absence of obesity or hyperlipidemia
Authors: Aubin Marie-Claude , Cardin Sophie , Comtois Philippe , Clément Robert , Gosselin Hugues , Gillis Marc-Antoine , Le Quang Khaï , Nattel Stanley , Perrault Louis P. , Calderone Angelino
Published: February 2010

Obesity increases the incidence of cardiac arrhythmias and impairs wound healing. However, it is presently unknown whether a high-fat diet affects arrhythmic risk or wound healing before the onset of overt obesity or hyperlipidemia. After 8 wk of feeding a high-fat diet to adult female rats, a nonsignificant increase in body weight was observed and associated with a normal plasma lipid profile. Following ischemia/reperfusion injury, scar length (standard diet 0.29 ± 0.09 vs. high-fat 0.32 ± 0.13 cm), thickness (standard diet 0.047 ± 0.02 vs. high-fat 0.059 ± 0.01 cm), and collagen α1 type 1 content (standard diet 0.21 ± 0.04 vs. high-fat 0.20 ± 0.04 arbitrary units/mm2) of infarcted hearts were not altered by the high-fat diet. However, the mortality rate was greatly increased 24 h postinfarction (from 5% to 46%, P < 0.01 for ischemia/reperfusion rats; from 20% to 89%, P < 0.0001, in complete-occlusion rats) in high-fat fed rats, in association with a higher prevalence of ventricular arrhythmias. Ventricular arrhythmia inducibility was also significantly increased in noninfarcted rats fed a high-fat diet. In the hearts of rats fed a high-fat diet, connexin-40 expression was absent, connexin-43 was hypophosphorylated and lateralized, and neurofilament-M immunoreactive fiber density (standard diet 2,020 ± 260 vs. high-fat diet 2,830 ± 250 μm2/mm2) and tyrosine hydroxylase protein expression were increased ( P < 0.05). Thus, in the absence of overt obesity and hyperlipidemia, sympathetic hyperinnervation and an aberrant pattern of gap junctional protein expression and regulation in the heart of female rats fed a high-fat diet may have contributed in part to the higher incidence of inducible cardiac arrhythmias.
The Responses of VIP Neurons Are Sufficiently Sensitive to Support Heading Judgments
Authors: Zhang Tao , Britten Kenneth H.
Published: February 2010

The ventral intraparietal area (VIP) of the macaque monkey is thought to be involved in judging heading direction based on optic flow. We recorded neuronal discharges in VIP while monkeys were performing a two-alternative, forced-choice heading discrimination task to relate quantitatively the activity of VIP neurons to monkeys' perceptual choices. Most VIP neurons were responsive to simulated heading stimuli and were tuned such that their responses changed across a range of forward trajectories. Using receiver operating characteristic (ROC) analysis, we found that most VIP neurons were less sensitive to small heading changes than was the monkey, although a minority of neurons were equally sensitive. Pursuit eye movements modestly yet significantly increased both neuronal and behavioral thresholds by approximately the same amount. Our results support the view that VIP activity is involved in self-motion judgments.
Tuberculous Infection of Thyroid Gland: A Case Report
Authors: Modayil Prince Cheriyan , Leslie Anna , Jacob Antony
Published: February 2010

Introduction. Tuberculosis is one of the leading causes of morbidity and mortality and almost one-third of the world is infected with this disease. Tuberculosis has been reported in many parts of the human body. But thyroid gland involvement is extremely rare and its true incidence is unknown.Case Presentation. We present the case of a 26-year-old woman who presented with a thyroid cyst which turned out to be a primary mycobacterium tuberculosis infection.Conclusion. The correct diagnosis of thyroid tuberculosis is important because of the availability of medical treatment and the limited role of surgery.
Cloning, Purification, and Partial Characterization ofBacillus subtilisUrate Oxidase Expressed inEscherichia coli
Authors: Pfrimer Pollyana , Moraes Lidia Maria Pepe de , Galdino Alexsandro Sobreira , Salles Loise Pedrosa , Reis Viviane Castelo Branco , De Marco Janice Lisboa , Prates Maura Vianna , Bloch Carlos , Torres Fernando Araripe Gonçalves
Published: February 2010

Urate oxidase (EC 1.7.3.3) is an enzyme involved in purine metabolism which is used in the treatment of gout and as diagnostic reagent for detection of uric acid. In order to produce this enzyme in large quantities for biotechnological purposes, the gene coding for theBacillus subtilisurate oxidase was cloned and heterologously expressed inEscherichia coli. Time course induction inE. colishowed an induced protein with an apparent molecular mass of∼60 kDa. Soluble recombinant enzyme was purified in a single-step procedure using Ni-NTA column. The enzyme was purified 2.1-fold with a yield of 56% compared to the crude extract. MALDI-TOF analysis revealed an ion with a mass of 58675 Da which is in agreement with the expected mass of the recombinant protein. The purified enzyme showed an optimal pH and temperature of 8.0 and37∘C, respectively, and retained 90% of its activity after 72 hours of incubation at −20∘Cand4∘C.
Sociodemographic Determinants for Oral Health Risk Profiles
Authors: Vanobbergen J. , De Visschere L. , Daems M. , Ceuppens A. , Van Emelen J.
Published: February 2010

The present study aimed to explore the association between caries risk profiles and different sociodemographic factors . The study sample () was randomly selected within an urban population in Flanders, Belgium. Caries risk was assessed by anamnesis, clinical examination, salivary tests, and a questionnaire. Age, gender, and socio-economic status were extracted from social insurance data files. Social indicators were “occupational status,” “being entitled to the increased allowance for health care interventions” and having access to the “Maximum Bill” (MAF), initiatives undertaken to protect deprived families. In the bivariate analysis there were significant differences in risk profiles between occupational groups (), between entitled and non-entitled individuals to the increased allowance (), and between access or no-access to the MAF (). The multiple logistic model showed a significantly higher chance of being in the low risk group for individuals with no-access to the MAF compared to those with access (OR:14.33–95% C.I. 2.14–95.84).
Endocannabinoid System Participates in Neuroendocrine Control of Homeostasis
Authors: De Laurentiis Andrea , Fernández Solari Javier , Mohn Claudia , Zorrilla Zubilete María , Rettori Valeria
Published: February 2010

The hypothalamo-neurohypophyseal system plays a role in homeostasis under a variety of stress conditions, including endotoxemia. Oxytocin (OXT) and vasopressin (VP) are important hormones synthesized by neurons in the hypothalamic paraventricular and supraoptic nuclei and released into different brain regions and from the neurohypophyseal terminals into the blood in response to many patho-physiological stimuli. However, the mechanism that controls OXT and VP secretion has not been fully elucidated. Nitric oxide (NO) is a known mediator that regulates the release of these hormones. The endocannabinoid system is a new intercellular system that modulates several neuroendocrine actions. Endocannabinoids (eCB) are released as retrograde messengers by many neurons, including hypothalamic magnocellular neurons and cannabinoid receptors are localized within these neurons, as well as in the anterior and posterior pituitary lobes, suggesting an eCB role in the production and release of OXT and VP. Lipopolysaccharide (LPS) injection is a model used as immune challenge. LPS causes a neuroendocrine response that is mediated by cytokines, tumor necrosis factor-α being one of them. We focused on NO and endocannabinoid system participation on OXT and VP production and secretion during basal and stress conditions and found that eCB affect basal OXT and VP secretion by acting differently at each level of the hypothalamo-neurohypophyseal system. After LPS, there is an increase in eCB synthesis that enhances OXT secretion.
Disease-Modifying Immunotherapy for the Management of Autoimmune Diabetes
Authors: Castro Carla N. , Barcala Tabarrozi Andres E. , Noguerol Maria Antunica , Liberman Ana C. , Dewey Ricardo A. , Arzt Eduardo , Morelli Adrian E. , Perone Marcelo J.
Published: February 2010

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that destroys the insulin-secreting β-cells of the pancreas. It is now possible to predict those candidates that will progress to T1D before the full onset of the disease. Prevention of uncontrollable autoimmunity against β-cells in therapies for T1D is mandatory to preserve the β-cell mass. Therefore, immunomodulatory strategies directed to inhibiting the activity of self-reactive T cell clones as well as induction of regulatory T cells would be beneficial for prevention of T1D or recurrence of β-cell autoimmunity against islet cell allografts.
Differential Regulation of IgG-NMO Autoantibodies on S100Beta Protein and Disability in Relapsing Neuromyelitis Optica
Authors: Robinson-Agramonte Maria A. , Gonçalves Carlos Alberto Saravia , Portela Valmor L. , Saiz-Hinarejos A. , Oses Pierre J. , Motta Souza L. , Muller A. Pastoris , Marquez Gonzalez M.E. , Gomes de Souza Onofre D.
Published: February 2010

Neuromyelitis optica (NMO), an uncommon central nervous system (CNS) demyelinating disease, produces transverse myelitis and severe optic neuritis. IgG-NMO autoantibody, a specific immunoglobulin binding aquaporin-4 water channel protein, confirms that NMO is a different entity to multiple sclerosis. Parallel to cytokine down-regulations found in serum of relapsing-NMO (rNMO) patients, it has been reported that IgG-NMO may also confer a worse course of the disease in r-NMO Caribbean patients. In this study, we were interested in exploring the influence of IgG-NMO autoantibody on S100β levels and clinical parameters from serum of r-NMO patients. Serum samples from 24 rNMO patients and 10 controls were evaluated. The reduction of S100β observed in r-NMO patients was not significant compared to controls; and no differences were present regarding IgG-NMO immunoreactivity. At the same time, a significant correlation was also observed between IgG-NMO autoantibody serum detection and EDSS (Expanded Disability Status Scale) in rNMO. These results corroborate a differential regulation of IgG-NMO autoantibodies on the S100β glial marker and on the disability present in rNMO patients.
Role of Toll-Like Receptors and Inflammation in Adrenal Gland Insufficiency
Authors: Kanczkowski Waldemar , Zacharowski Kai , Bornstein Stefan R.
Published: February 2010

Adrenal gland insufficiency – the clinical manifestation of deficient production or action of adrenal steroids – is a life-threatening disorder. Among many factors which can predispose to primary adrenal failure, an autoimmune adrenalitis and infectious agents play a major role. The initial host defense against bacterial infections is executed primarily by the pattern recognition receptors, e.g. Toll-like receptors (TLRs), expressed in cells from the innate immune system. Upon activation, TLRs have been found to regulate various levels of innate and adaptive immunity as well as control tissue inflammation. TLRs are implicated in adrenal cell turnover and steroidogenesis during inflammation. Therefore, TLRs play a crucial role in the activation of adrenal inflammation mediating adrenal gland dysfunction during septicemia.
Neuroimmune Interactions in Stress
Authors: Costa-Pinto Frederico A. , Palermo-Neto João
Published: February 2010

Stress has long been recognized as a putative modulator of immunity. Several clinical and experimental reports point to a role of physical and psychological stressors on progression or resistance to disease. Nonetheless, literature in this field is sometimes controversial due to the wide variety of stressors employed and parameters of immunity analyzed. This variation should not be considered a consequence of methodological inaccuracy. The stress response, although theoretically stereotyped in nature, may lead to slightly different outcomes according to several modifiers. Our group has compared the effects of several stressors over different parameters of brain activity, behavior, immunity and glucocorticoid levels. These data show altogether that while increased turnover of noradrenaline in the hypothalamus, along with anxiety-like behaviors and increase in serum corticosterone are present very often, the magnitude of changes in immunity may vary considerably. Thus, we review data from our group generated over the past decade to support that effects of stressors on immunity and behavior highly depend on their specifics, animal model, frequency, duration, intensity, perception, and coping by the stressed animal.
Muscle MRI in Myotonic Dystrophy Type 1 with Foot Drop
Authors: Hamano Tadanori , Kawamura Yasutaka , Mutoh Tatsuro , Hirayama Mikio , Kuriyama Masaru
Published: February 2010

The purpose of this study was to investigate the relationship of muscle MRI findings and gait disturbance in myotonic dystrophy type 1 (DM1) patients. Thirteen patients with DM1 were evaluated by manual muscle strength test and muscle MRI of the lower limb. All DM1 patients presenting with foot drop showed high intensity signals in the tibialis anterior muscles on T1-weighted imaging (p < 0.001). The patients presenting with gait disturbance showed high intensity signals in the semimembranosus, vastus intermedius and gastrocnemius medialis muscles, too. Disturbance of the gastrocnemius lateralis muscles was mild in all DM1 patients. The patients without gait disturbance showed no abnormalities, especially in tibialis anterior muscles on muscle MRI. Muscle MRI is useful for the detection of pathological muscles in DM1 patients with gait disturbance.
Corticospinal Tract Change in the Unaffected Hemisphere at the Early Stage of Intracerebral Hemorrhage: A Diffusion Tensor Tractography Study
Authors: Kwak So Young , Yeo Sang Seok , Choi Byung Yeon , Chang Chul Hoon , Jang Sung Ho
Published: February 2010

Objectives: Contribution by the unaffected hemisphere is one of the motor recovery mechanisms following stroke. We attempted to investigate changes in the corticospinal tract (CST) in the unaffected hemisphere at the early stage in patients with intracerebral hemorrhage (ICH), using diffusion tensor tractography (DTT). Subjects and Methods: Fifty-three consecutive hemiparetic patients and 40 age- and sex-matched control subjects were enrolled. DTT was performed using a 1.5-tesla system at the early stage of ICH (7–28 days after onset). We measured the fiber number, fractional anisotropy and apparent diffusion coefficient of CST tractography in the unaffected hemisphere, and assessed the motor function of the affected extremities. Results: The fiber number of the CST in the unaffected hemisphere of the patient group was higher than that of the control group (p = 0.000). In contrast, the fractional anisotropy value was lower than that of the control group (p = 0.018). However, there were no significant differences in the apparent diffusion coefficient values between the 2 groups (p = 0.654). Conclusions: We demonstrated that the CST in the unaffected hemisphere was changed at the early stage in patients with ICH, using DTT.
Assessment of laboratory assays to measure rivaroxaban – an oral, direct factor Xa inhibitor
Authors: Martinoli Jean-Luc , LeFlem Léna , Guinet Céline , Plu-Bureau Geneviève , Depasse François , Perzborn Elisabeth , Samama Meyer Michel
Published: February 2010

Although there is no need for routine coagulation monitoring with rivaroxaban – an oral, direct factor Xa inhibitor – a haemostasis assay might be valuable to measure its pharmacodynamic effects. This study aimed to find assays, among those commercially available, to measure rivaroxaban pharmacodynamics. Several global conventional clotting tests, as well as clotting or chromogenic assays to measure anti-factor Xa activity, were studied. A thrombin generation test using calibrated automated thrombogram was also done. Tests were performed with the indirect factor Xa inhibitor fondaparinux for comparison. A concentration-dependent prolongation of prothrombin time (PT), dilute PT, and activated partial thromboplastin time was observed with rivaroxaban. The results varied depending on the reagents. This variability cannot be standardised with the international normalised ratio system commonly used for vitamin K antagonists. Using a standard calibration curve, PT test results can be expressed in plasma concentrations of rivaroxaban rather than PT seconds or ratio. Standard methods for HepTest and two-step prothrombinase-induced clotting time (PiCT) resulted in a paradoxical response, with low concentrations of rivaroxaban reducing clotting times. This was not observed with shorter incubation times, or when antithrombin-deficient (immunodepleted) plasma was used. The chromogenic tests found a dose-dependent relationship between anti-factor Xa activity and rivaroxaban concentration. Modified specific factor Xa chromogenic assays are being further investigated. One-step PiCT and HepTest with shortened incubation times, as well as the widely available PT assay (using a rivaroxaban calibrator) could be useful to monitor the pharmacodynamic effects of rivaroxaban accurately. Finally, all clotting and chromogenic assays showed a concentration-dependent effect induced by rivaroxaban.
8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties
Authors: Grandoch Maria , Börgermann Christof , Oude Weernink Paschal , Mahlke Yvonne , Schwindenhammer Benjamin , Weber Artur-Aron , Fischer Jens , Jakobs Karl , Sand Carsten , Schmidt Martina
Published: February 2010

Membrane-permeable 8-(4-chlorophenylthio)-2'-O-methyl cyclic AMP (8-pCPT-2'-O-Me-cAMP) has been shown to specifically activate cAMP-regulated Epac proteins, without direct effects on protein kinase A and protein kinase G. During isometric tension measurements in thoracic aortic rings from Wistar rats, we observed that 8-pCPT-2'-O-Me-cAMP selectively induced a rightward shift of the concentration response curve for the thromboxane mimetic U46619, without altering the contractile response to noradrenaline. We hypothesised that 8-pCPT-2'-O-Me-cAMP and similar compounds may function as direct thromboxane receptor antagonists. Indeed, in addition to 8-pCPT-2'-OMe-cAMP, also 8-pCPT-cAMP, 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-CPT-cAMPS) and 8-CPT-adenosine, but not 8-Bromo-2'-O-Me-cAMP, induced rightward shifts of the contractile response to U46619. Likewise, 8-pCPT-2'-O- Me-cAMP and Rp-8-CPT-cAMPS, but not 8-Bromo-2'-O-Me-cAMP, specifically reduced U46619-induced aggregation of human platelets. In addition, 8-pCPT-2'-O-Me-cAMP and Rp-8-CPT-cAMPS completely reversed U46619-induced reduction of intercellular adhesion molecule-1 expression and migration of human coronary artery endothelial cells. Most important, the cAMP analogs that reduced the contractile response to U46619 also concentration-dependently inhibited binding of the thromboxane receptor radioligand [5,6-3H]SQ29548 to human platelets. We conclude that 8-pCPT-conjugated cAMP analogs exert competitive thromboxane receptor antagonistic properties.
Adrenergic receptor polymorphisms and platelet reactivity after treatment with dual antiplatelet therapy with aspirin and clopidogrel in acute coronary syndrome
Authors: Cuisset Thomas , Hamilos Michalis , Delrue Leen , Frere Corinne , Verhamme Katia , Bartunek Jozef , Saut Noemie , Bonnet Jean Louis , Eijgelsheim Mark , Wijns William , Alessi Marie-Christine , Barbato Emanuele
Published: February 2010

Platelet response to clopidogrel shows inter-individual variability that is partially explained by genetic polymorphisms. This variability affects clinical outcome when clopidogrel is administered in patients with acute coronary syndrome (ACS). Catecholamines, released during ACS, contribute to platelet aggregation through platelet α2A- (α2A-AR) and β2-adrenergic receptor (β2-AR) stimulation. It was the objective of this study to assess the potential influence of α2A-AR and β2-AR gene polymorphisms on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel in ACS. We screened 641 ACS patients for 6.3/6.7 kb α2A-AR polymorphism, and for Arg16Gly and Gln27Glu β2-AR polymorphism. After 600 mg clopidogrel, we assessed ADP 10 μmol-induced platelet aggregation (ADP-Ag) and vasoactive stimulated phosphoprotein (VASP). All single nucleotide polymorphisms were in Hardy-Weinberg equilibrium. A slight though negligible association was found between 6.3 kb allele of α2A-AR with platelet reactivity ADPAg induced (beta: –2.91 [-5.68;-0.14], p=0.04). A borderline not significant reduction in PRI VASP was observed in 6.3 kb α2A-AR carriers (beta: –3.81 [-0.09;7.72], p=0.06). No significant effect on platelet parameters was observed for the other tested polymorphisms. Common α2A- and β2-adrenergic receptor polymorphisms do not show any major impact on residual platelet reactivity in non-ST-elevation ACS when a dual antiplatelet therapy with 250 mg aspirin and 600 mg clopidogrel is administered.
Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells
Authors: Albiñana Virginia , Bernabeu-Herrero Maria , Zarrabeitia Roberto , Bernabeu Carmelo , Botella Luisa
Published: February 2010

Hereditary haemorrhagic telangiectasia (HHT), or Rendu-Osler-Weber syndrome, is an autosomal dominant vascular disease. The clinical manifestations are epistaxis, mucocutaneous and gastrointestinal telangiectases, and arteriovenous malformations. There are two predominant types of HHT caused by mutations in Endoglin (ENG) and activin receptor-like kinase 1 (ALK1) (ACVRL1) genes, HHT1 and HHT2, respectively. No cure for HHT has been found and there is a current need to find new effective drug treatments for the disease. Some patients show severe epistaxis which interferes with their quality of life. We report preliminary results obtained with Raloxifene to treat epistaxis in postmenopausal HHT women diagnosed with osteoporosis. We tried to unravel the molecular mechanisms involved in the therapeutic effects of raloxifene. ENG and ACVRL1 genes code for proteins involved in the transforming growth factor β pathway and it is widely accepted that haploinsufficiency is the origin for the pathogenicity of HHT. Therefore, identification of drugs able to increase the expression of those genes is essential to propose new therapies for HHT. In vitro results show that raloxifene increases the protein and mRNA expression of ENG and ALK1 in cultured endothelial cells. Raloxifene also stimulates the promoter activity of these genes, suggesting a transcriptional regulation of ENG and ALK1. Furthermore, Raloxifene improved endothelial cell functions like tubulogenesis and migration in agreement with the reported functional roles of Endoglin and ALK1. Our pilot study provides a further hint that oral administration of raloxifene may be beneficial for epistaxis treatment in HHT menopausal women. The molecular mechanisms of raloxifene involve counteracting the haploin-sufficiency of ENG and ALK1.
Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and apixaban in preclinical and clinical development
Authors: Ufer Mike
Published: February 2010

Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and apixaban throughout preclinical and clinical development.
Antithrombotic treatment and the risk of death and stroke in patients with atrial fibrillation and a CHADS2 score=1
Authors: Gorin Laurent , Nonin Emilie , Labriolle Axel de , Haguenoer Ken , Cosnay Pierre , Babuty Dominique , Charbonnier Bernard , Fauchier Laurent
Published: February 2010

In patients with atrial fibrillation (AF) and an intermediate risk of stroke (CHADS2 score =1), available evidence from clinical trials is inconclusive and the present guidelines for the management of AF indicate that the choice between oral anticoagulant and aspirin in these patients is open. Our goal was to evaluate whether, in patients with AF and only one moderate risk factor for thromboembolism, treatment with an oral anticoagulant is appreciably more beneficial than treatment with an antiplatelet agent. Among 6,517 unselected patients with AF, 1,012 of them (15.5%) had a CHADS2 score of 1 and were liable to treatment with an antiplatelet agent or an anticoagulant. An oral anticoagulant was prescribed for 606 patients (59.9%) and an antiplatelet agent or no antithrombotic treatment for 406 (40.1%). During follow-up (median=793 days, interquartile range=1,332 days), 105 deaths (10.4%) and 19 strokes (1.9%) were recorded. The administration of an anticoagulant was associated with a lower rate of events (relative risk=0.42, 95% confidence interval 0.29–0.60, p<0.0001) than when no anticoagulant was prescribed. Results remained similar after adjustment for age and other confounding factors. In contrast, prescription of an antiplatelet agent was not associated with a lower risk of events. Factors independently associated with an increased risk of events were older age (p<0.0001), concomitant heart failure (p=0.0002), diabetes (p=0.0025), lack of prescription of an anticoagulant (p<0.0001) and permanent AF (p=0.04). Thus, prescription of an anticoagulant is independently associated with a decreased risk of death or stroke among patients with AF and a CHADS2 score =1.
Genetic Association of the CCR5 Region With Lipid Levels in At-Risk Cardiovascular Patients
Authors: Hyde Craig L. , MacInnes Alan , Sanders Frances A. , Thompson John F. , Mazzarella Richard A. , Faergeman Ole , van Wijk Diederik F. , Wood Linda , Lira Maruja , Paciga Sara A.
Published: February 2010

Background—

There is mounting evidence to suggest that chemokine receptor 5 (CCR5) plays an important role in the development and progression of atherosclerosis. A naturally occurring variant of the
CCR5
gene CCR532, exists at allele frequencies of typically 10% in European populations and results in a nonfunctional CCR5 receptor.

Methods and Results—

The CCR5Δ32 deletion and 26 other variants within the chemokine receptor 2
-CCR5-
chemokine receptor-like protein 2 (
CCRL2
) gene cluster spanning 59 kilobases of chromosome 3 were genotyped in 5748 subjects from the Treating to New Targets atorvastatin trial to determine whether genetic associations could be identified with circulating lipid values and cardiovascular disease. Our results demonstrate an association between the CCR5Δ32 deletion and increased plasma high-density lipoprotein cholesterol and decreased plasma triglycerides, both of which are beneficial from a cardiovascular perspective. Three single-nucleotide polymorphisms (rs1154428, rs6808835, and rs6791599) in
CCRL2
in linkage disequilibrium (r
2
≥0.65) with CCR5Δ32 and located up to 45 kilobases distal to it were associated with high-density lipoprotein cholesterol. The high-density lipoprotein cholesterol and triglycerides findings were replicated in an additional set of >6000 individuals from the Incremental Decrease in Endpoints through Aggressive Lipid Lowering atorvastatin trial.

Conclusions—

Our study provides evidence that a locus within the region of the genome encompassing the CCR5-CCRL2 region is associated with lipid levels and suggests that chemokine activity influences lipid levels in populations with preexisting cardiovascular disease.

Clinical Trial Registration—

clinicaltrials.gov. Identifier: TNT, NCT00327691; IDEAL, NCT00159835.
Development of the Pacemaker Tissues of the Heart
Authors: Christoffels Vincent M. , Smits Gertien J. , Kispert Andreas , Moorman Antoon F. M.
Published: February 2010

Pacemaker and conduction system myocytes play crucial roles in initiating and regulating the contraction of the cardiac chambers. Genetic defects, acquired diseases, and aging cause dysfunction of the pacemaker and conduction tissues, emphasizing the clinical necessity to understand the molecular and cellular mechanisms of their development and homeostasis. Although all cardiac myocytes of the developing heart initially possess pacemaker properties, the majority differentiates into working myocardium. Only small populations of embryonic myocytes will form the sinus node and the atrioventricular node and bundle. Recent efforts have revealed that the development of these nodal regions is achieved by highly localized suppression of working muscle differentiation, and have identified transcriptional repressors that mediate this process. This review will summarize and reflect new experimental findings on the cellular origin and the molecular control of differentiation and morphogenesis of the pacemaker tissues of the heart. It will also shed light on the etiology of inborn and acquired errors of nodal tissues.
Protein Acetylation in the Cardiorenal Axis
Authors: Bush Erik W. , McKinsey Timothy A.
Published: February 2010

Abstract
:

Acetylation of histone and nonhistone proteins provides a key mechanism for controlling signaling and gene expression in heart and kidney. Pharmacological inhibition of protein deacetylation with histone deacetylase (HDAC) inhibitors has shown promise in preclinical models of cardiovascular and renal disease. Efficacy of HDAC inhibitors appears to be governed by pleiotropic salutary actions on a variety of cell types and pathophysiological processes, including myocyte hypertrophy, fibrosis, inflammation and epithelial-to-mesenchymal transition, and occurs at compound concentrations below the threshold required to elicit toxic side effects. We review the roles of acetylation/deacetylation in the heart and kidney and provide rationale for extending HDAC inhibitors into clinical testing for indications involving these organs.
How Selfish Are Self-Expression Values? A Civicness Test
Authors: Welzel Christian
Published: February 2010

Various analyses of World Values Survey data find a syndrome of emancipative orientations, mostly known as “self-expression values,” on the rise throughout all countries with longitudinal evidence. But, as much as scholarship agrees on the rise of self-expression values, there is disagreement on whether these values are civic or uncivic in character. Some declare self-expression values uncivic because they see them as indicative of egoism and weak social capital. Others consider self-expression values as civic for the opposite reasons. They interpret them as a sign of altruism and strong social capital. Cross-cultural evidence from the World Values Surveys supports the civic view on both accounts. First, in a Schwartz value space, self-expression values are associated with altruism, especially at high levels of self-expression values. Second, in a social capital space, self-expression values go together with trust in people and peaceful collective action. The findings qualify self-expression values as a civic form of modern individualism.
Brazilian Mothers’ Beliefs About Child-Rearing Practices
Authors: Vieira Mauro Luís , Seidl-de-Moura Maria Lucia , Lordelo Eulina , Piccinini Cesar Augusto , Dal Forno Martins Gabriela , Mafioletti Macarini Samira , Ribeiro Moncorvo Maria Cecília , Ramos Pontes Fernando Augusto , Colino Magalhães Celina Maria , Ribeiro Salomão Nádia Maria , Odália Rimoli Adriana
Published: February 2010

Mothers’ beliefs about their practices in different Brazilian contexts were investigated in this study. A sample of 350 primiparous Brazilian mothers from seven cities, each from one of the five geographic regions of the country, participated in this study. As part of a major project, mothers answered an inventory concerning their beliefs about practices of child care and a sociodemographic questionnaire. Factorial analysis revealed three factors, named Proper Presentation (the importance mothers attribute to parental practices oriented by socially accepted daily rules), Stimulation (the importance attributed by mothers to practices that stimulate their children’s development), and Responsiveness and Bonding (the importance attributed by mothers to the immediate responses to children’s needs and to a bond of intense proximity and protection).The sample studied valued most Proper Presentation, followed by Stimulation. Less importance was attributed to Responsiveness and Bonding. Mothers’ educational level was a predictor of scores on Stimulation, and fathers’ educational level was a predictor of scores on Proper Presentation. Some regional differences were identified regarding Proper Presentation. A general model that encompasses aspects of socialization for group interaction and also cognitive and social stimulation seems to be shared by mothers of the different geographic regions of the country. This model is influenced by educational level and cultural conditions. Future studies need to address the development of instruments to analyze Brazilian parental cultural models and the implications of these models to children’s development.