bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertical Transmission of Bovine Spongiform Encephalopathy Prions Evaluated in a Transgenic Mouse Model
Authors: Castilla J. , Brun A. , Díaz-San Segundo F. , Salguero F. J. , Gutiérrez-Adán A. , Pintado B. , Ramírez M. A. , del Riego L. , Torres J. M.
Published: June 2005

In this work we show evidence of mother-to-offspring transmission in a transgenic mouse line expressing bovine PrP (boTg) experimentally infected by intracerebral administration of bovine spongiform encephalopathy (BSE) prions. PrPreswas detected in brains of newborns from infected mothers only when mating was allowed near to the clinical stage of disease, when brain PrPresdeposition could be detected by Western blot analysis. Attempts to detect infectivity in milk after intracerebral inoculation in boTg mice were unsuccessful, suggesting the involvement of other tissues as carriers of prion dissemination. The results shown here prove the ability of BSE prions to spread centrifugally from the central nervous system to peripheral tissues and to offspring in a mouse model. Also, these results may complement previous epidemiological data supporting the occurrence of vertical BSE transmission in cattle.
Painting as policy
Authors: Etheredge J A
Published: June 2005

Ours is, at its heart, a profession of service predicated on mutual trust. All too often policies aimed at resolving a particular problem in health care are inadequate not because they fail at what they were intended to do, but rather because of the unintended consequences, both direct and indirect, that are inevitable in complex systems where competing interests preclude unity of purpose. Ultimately, these policy “layers” distance us from our foundational principles and the disjointed complexity that ensues alienates the patient, disheartens and disillusions the physician, and further undermines the relationship that is so crucial to proper health care delivery. Importantly, we must realise that legislative complexity simply cannot make up for an absence of trust and instead work to foster such trust by reflecting our profession’s tradition of service to the public through a blatant, highly visible pursuit of patient welfare.
THE BONDING PROPERTIES OF AMORPHOUS CARBON NITRIDE FILMS BY THE MEANS OF X-RAY PHOTOELECTRON SPECTROSCOPY STUDIES
Authors: RUSOP M. , SOGA T. , JIMBO T.
Published: June 2005

Amorphous carbon nitride films (a -CNx) were deposited by pulsed laser deposition of camphoric carbon target at different substrate temperatures (ST). The influence of ST on the bonding properties of a -CNxfilms was investigated. The nitrogen to carbon (N/C) atomic ratio and oxygen to carbon (O/C) atomic ratio, bonding state and microstructure of the deposited a -CNxfilms were characterized by X-ray photoelectron spectroscopy and confirmed by other standard measurement techniques. The bonding states between the C and N, and C and O in the deposited films are found significantly influenced by the ST during deposition process. The N/C and O/C atomic ratio of the a -CNxfilms reached the maximum value at 400°C. The ST of 400°C was proposed to promote the desired sp3-hybridized C and the C3N4phase. The C–N bonding of C–N, C=N and C–N were observed in the deposited a -CNxfilms.
SLOW ELECTRONS PENETRATION IN GOLD AT NORMAL AND OBLIQUE ANGLES OF INCIDENCE
Authors: CHAOUI Z. , BOUARISSA N.
Published: June 2005

Electron penetration in semi-infinite Au for normal and oblique angles of incidence at energies between 0.5 and 4 keV is simulated within a Monte-Carlo frame work. The elastic scattering cross sections have been obtained from a modified Rutherford differential cross section, whereas inelastic core and valence electron excitation are calculated using the Gryzinski's expression. The dependence of the backscattering coefficient, mean implantation depth and stopping profiles on the angle of incidence has been examined. These quantities are found to be significantly enhanced as the angle of incidence becomes higher which is generally in consistent with previous simulations.
EVALUATION OF BISTABLE SYSTEMS VERSUS MATCHED FILTERS IN DETECTING BIPOLAR PULSE SIGNALS
Authors: DUAN FABING , ABBOTT DEREK , GAO QISHENG
Published: June 2005

This paper presents a thorough evaluation of a bistable system versus a matched filter in detecting bipolar pulse signals. The detectability of the bistable system can be optimized by adding noise, i.e. the stochastic resonance (SR) phenomenon. This SR effect is also demonstrated by approximate statistical detection theory of the bistable system and corresponding numerical simulations. Furthermore, the performance comparison results between the bistable system and the matched filter show that (a) the bistable system is more robust than the matched filter in detecting signals with disturbed pulse rates, and (b) the bistable system approaches the performance of the matched filter in detecting unknown arrival times of received signals, with an especially better computational efficiency. These significant results verify the potential applicability of the bistable system in signal detection field.
MEASURES AND INDICES FOR INTRINSIC CHARACTERIZATION OF CARDIAC DYSFUNCTION DURING FILLING AND SYSTOLIC EJECTION
Authors: ZHONG LIANG , GHISTA DHANJOO N. , NG E. Y.-K. , LIM SOO TEIK , CHUA SIANG JIN
Published: June 2005

The paper discusses the development and application of bioengineering indices for reliable diagnosis of cardiac functional modalities in filling and contraction phases.

During diastolic filling, the left-ventricular (LV) volume developed is a response to left-atrium (LV) suction at early rapid filling and LA contraction at late filling. However, in LV ejection, the LV flow-rate and aortic pressure constitute response to LV myocardial stress and intra-LV pressure generation. The differential equations used in the governing of these relationships have been developed. By matching the solutions of these differential equations with the clinical data of LV volume and pressure, we can determine the heart model "differential equations" parameters, as well as the derived indices. These parameters and indices include: compliance and resistance-to-filling for characterizing diastolic-filling function, together with the index of LV contractility (in terms of maximum LV contractile power and stress-velocity relationship for contractile element). By evaluating them, it is possible to diagnose more reliably and differentially heart diseases due to an increase in filling-resistance and contractility abnormalities.
The Three-Phase Interstellar Medium Revisited
Authors: Cox Donald P.
Published: June 2005

▪ Abstract  The interstellar medium in the vicinity of the Sun is arranged in large-scale structures of bubble walls, sheets, and filaments of warm gas, within which close to the midplane there are subsheets and filaments of cold dense material; the whole occupies roughly half the available volume and extends with decreasing mean density to at least a kiloparsec off the plane. The remainder of the volume is in bubble interiors, cavities, and tunnels of much lower density, with some but not all of those lower density regions hot enough to be observable via their X-ray emission. This entire system is pervaded by a rather strong and irregular magnetic field and cosmic rays, the pressures of which are confined by the weight of the interstellar gas, particularly that far from the plane where gravity is strong. Observations suggest that the cosmic rays and magnetic field have an even more extended vertical distribution than the warm gas, requiring either the weight of additional coronal material or magnetic tension to confine it to the disk. Adjusting one's perception of this medium to embrace the known aspects is difficult. After this adjustment, there are many problems to solve and prejudices to overcome—the weak role of thermal instability, the suppression of certain gravitational instabilities, the problem of determining the state in the low-density regions, the twin difficulties of not having too much OVI (O+5) and getting enough diffuse 3/4 keV X-ray emission, the possible importance of large old-barrel–shaped supernova remnants in clarifying matters, the possible role of dust evolution in adjusting the heating to make clouds stable, the factors influencing the magnitudes of the interstellar pressure and scale height—things that global models of the medium might examine to clarify some of these matters; attention to these details and more constitute the challenge of this subject.
Centrally administered adrenomedullin 2 activates hypothalamic oxytocin-secreting neurons, causing elevated plasma oxytocin level in rats
Authors: Hashimoto Hirofumi , Hyodo Susumu , Kawasaki Makoto , Mera Takashi , Chen Lei , Soya Atsushi , Saito Takeshi , Fujihara Hiroaki , Higuchi Takashi , Takei Yoshio , Ueta Yoichi
Published: June 2005

We examined the effects of intracerebroventricular (ICV) administration of adrenomedullin 2 (AM2) on plasma oxytocin (OXT) and arginine vasopressin (AVP) levels in conscious rats. Plasma OXT levels were markedly increased 5 min after ICV administration of AM2 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 10, 15, 30, and 60 min. By contrast, plasma AVP levels were not significantly elevated in samples taken between 5 and 180 min after ICV administration of AM2 except at the 30-min time point. Fos-like immunoreactivity (Fos-LI) was observed in various brain areas, including the paraventricular (PVN) and the supraoptic nuclei (SON) after ICV administration of AM2 (2 nmol/rat) in conscious rats (measured at 90 min post-AM2 infusion). Dual immunostaining for OXT/Fos and AVP/Fos showed that OXT-LI neurons predominantly exhibited nuclear Fos-LI compared with AVP-LI neurons in the PVN and the SON. In situ hybridization histochemistry showed that ICV administration of AM2 (0.2, 1, and 2 nmol/rat) caused marked induction of the expression of the c- fos gene in the PVN and the SON. This induction was significantly reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8–37) (3 nmol/rat) and the AM receptor antagonist AM-(22–52) (27 nmol/rat). These results suggest that centrally administered AM2 mainly activates OXT-secreting neurons in the PVN and the SON, at least in part through the CGRP and/or AM receptors with marked elevation of plasma OXT levels in conscious rats.
Comparative analysis of ACTH and corticosterone sampling methods in rats
Authors: Vahl Torsten P. , Ulrich-Lai Yvonne M. , Ostrander Michelle M. , Dolgas C. Mark , Elfers Eileen E. , Seeley Randy J. , D'Alessio David A. , Herman James P.
Published: June 2005

A frequently debated question for studies involving the measurement of stress hormones in rodents is the optimal method for collecting blood with minimal stress to the animal. Some investigators prefer the implantation of indwelling catheters to allow for frequent sampling. Others argue that the implantation of a catheter creates a chronic stress to the animal that confounds stress hormone measures and therefore rely on tail vein sampling. Moreover, some investigators measure hormones in trunk blood samples obtained after anesthesia, a practice that may itself raise hormone levels. To address these controversies, we 1) compared plasma ACTH and corticosterone (Cort) concentrations in pre- and poststress rat blood samples obtained via previously implanted vena cava catheters, tail vein nicks, or clipping the tip off the tail and 2) compared plasma ACTH and Cort in rat blood samples obtained by decapitation with and without anesthesia. Rats sampled via indwelling catheters displayed lower prestress ACTH levels than those sampled by tail vein nick if the time to acquire samples was not limited; however, elevated basal ACTH was not observed in samples obtained by tail clip or tail nick when the samples were obtained within 3 min. Baseline Cort levels were similar in all groups. After restraint stress, the profile of the plasma ACTH and Cort responses was not affected by sampling method. Decapitation with prior administration of CO2 or pentobarbital sodium increased plasma ACTH levels ∼13- and 2-fold, respectively, when compared with decapitation without anesthesia. These data indicate that tail vein nicking, tail clipping, or indwelling venous catheters can be used for obtaining plasma for ACTH and Cort during acute stress studies without confounding the measurements. However, the elevation in basal ACTH seen in the tail vein nick group at baseline suggests that sampling needs to be completed rapidly (<3 min) to avoid the initiation of the pituitary stress response. Death by CO2 and pentobarbital sodium injection before trunk blood collection cause significant stress to animals, as reflected in the elevated plasma ACTH levels. These results support the use of either chronic vascular cannulas or sampling from a tail vein. However, collection of blood under pentobarbital sodium or CO2 anesthesia is likely to confound the results of stress studies when ACTH is an important endpoint.
Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs
Authors: Martini Wenjun Z. , Chinkes David L. , Pusateri Anthony E. , Holcomb John B. , Yu Yong-Ming , Zhang Xiao-Jun , Wolfe Robert R.
Published: June 2005

Hemorrhagic coagulopathy is involved in the morbidity and mortality of trauma patients. Nonetheless, many aspects of the mechanisms underlying this disorder are poorly understood. We have therefore investigated changes in fibrinogen metabolism and coagulation function after a moderate hemorrhagic shock, using a new stable isotope approach. Twelve pigs were randomly divided into the control (C) and hemorrhage (H) groups. Hemorrhage was induced by bleeding 35% total blood volume over a 30-min period. A primed constant infusion of [1-13C]phenylalanine (Phe), d5-phenylalanine, and α-[1-13C]-ketoisocaproate (KIC) was given to quantify fibrinogen synthesis and breakdown, together with measurements of circulating liver enzyme activities and coagulation function. Mean arterial pressure was decreased by hemorrhage from 89 ± 4 mmHg in C to 47 ± 4 mmHg in H ( P < 0.05), followed by a rebound to 68 ± 5 mmHg afterward. Fibrinogen fractional synthesis rate increased from 2.7 ± 0.2%/h in C to 4.2 ± 0.4%/h in H by Phe ( P < 0.05) and from 3.1 ± 0.4%/h in C to 4.4 ± 0.5%/h in H by KIC ( P < 0.05). Fibrinogen fractional breakdown rate increased from 3.6 ± 1.0%/h in C to 12.9 ± 1.8%/h in H ( P < 0.05). The absolute breakdown rate accelerated from 3.0 ± 0.4 mg·kg−1·h−1 in C to 5.4 ± 0.6 mg·kg−1·h−1 in H ( P < 0.05), but the absolute synthesis rate remained unchanged. These metabolic changes were accompanied by a reduction in blood clotting time to 92.7 ± 1.6% of the baseline value by hemorrhage ( P < 0.05). No changes were found in liver enzyme activities. We conclude that the observed changes in coagulation after hemorrhagic shock are mechanistically related to the acute acceleration of fibrinogen degradation.
AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats
Authors: Assifi Murwarid M. , Suchankova Gabriela , Constant Scarlet , Prentki Marc , Saha Asish K. , Ruderman Neil B.
Published: June 2005

Acute increases in the concentration of malonyl-CoA play a pivotal role in mediating the decrease in fatty acid oxidation that occurs in many tissues during refeeding after a fast. In this study, we assess whether such increases in malonyl-CoA in liver could be mediated by malonyl-CoA decarboxylase (MCD), as well as acetyl-CoA carboxylase (ACC). In addition, we examine how changes in the activity of ACC, MCD, and other enzymes that govern fatty acid and glycerolipid synthesis relate temporally to alterations in the activities of the fuel-sensing enzyme AMP-activated protein kinase (AMPK). Rats starved for 48 h and refed a carbohydrate chow diet for 1, 3, 12, and 24 h were studied. Refeeding caused a 40% decrease in the activity of the α1-isoform of AMPK within 1 h, with additional decreases in AMPKα1 activity and a decrease in AMPKα2 occurring between 1 and 24 h. At 1 h, the decrease in AMPK activity was associated with an eightfold increase in the activity of the α1-isoform of ACC and a 30% decrease in the activity of MCD, two enzymes thought to be regulated by AMPK. Also, the concentration of malonyl-CoA was increased by 50%. Between 1 and 3 h of refeeding, additional increases in the activity of ACC and decreases in MCD were observed, as was a further twofold increase in malonyl-CoA. Increases in the activity (60%) and abundance (12-fold) of fatty acid synthase occurred predominantly between 3 and 24 h and increases in the activity of mitochondrial sn-glycerol-3-phosphate acyltransferase (GPAT) and acyl-CoA:diaclyglycerol acyltransferase (DGAT) at 12 and 24 h. The results strongly suggest that early changes in the activity of MCD, as well as ACC, contribute to the increase in hepatic malonyl-CoA in the starved-refed rat. They also suggest that the changes in these enzymes, and later occurring increases in enzymes regulating fatty acid and glycerolipid synthesis, could be coordinated by AMPK.
PKC-induced ERK1/2 interactions and downstream effectors in ovine cerebral arteries
Authors: Zhao Yu , Zhang Lubo , Longo Lawrence D.
Published: June 2005

Both protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) are involved in mediating vascular smooth muscle contraction. We tested the hypotheses that in addition to PKC activation of ERK1/2, by negative feedback ERKs modulate PKC-induced contraction, and that their interactions modulate both thick and thin myofilament pathways. In ovine middle cerebral arteries (MCA), we measured isometric tension and intracellular free calcium concentration ([Ca2+]i) responses to PKC stimulation [phorbol 12,13-dibutyrate (PDBu), 3 × 10−6M] in the absence or presence of ERK1/2 inhibition (U-0126, 10−5M). After PDBu ± ERK1/2 inhibition, we also examined by Western immunoblot the levels of total and phosphorylated ERK1/2, caldesmonSer789, myosin light chain20(MLC20), and CPI-17. PDBu induced significant increase in tension in the absence of increased [Ca2+]i. PDBu also increased phosphorylated ERK1/2 levels, a response blocked by U-0126. In turn, U-0126 augmented PDBu-induced contractions. PDBu also was associated with significant increases in phosphorylated caldesmonSer789and MLC20levels, each of which peaked at 5 to 10 min. PDBu also increased phosphorylated CPI-17 levels, which peaked at 2 to 3 min. Rho kinase inhibition (Y-27632, 3 × 10−7M) did not alter PDBu-induced contraction. These results support the idea that PKC activation can increase CPI-17 phosphorylation to decrease myosin light chain phosphatase activity. In turn, this increases MLC20phosphorylation in the thick filament pathway and increases Ca2+sensitivity. In addition, ERK1/2-dependent phosphorylation of caldesmonSer789was not necessary for PDBu-induced contraction and appears not to be involved in the reversal of caldesmon's inhibitory effect on actin-myosin ATPase.
Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination
Authors: Yang Shuo , Chintapalli Janaki , Sodagum Lakshmi , Baskin Stuart , Malhotra Ashwani , Reiss Krzysztof , Meggs Leonard G.
Published: June 2005

The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.
Influence of Path Integration Versus Environmental Orientation on Place Cell Remapping Between Visually Identical Environments
Authors: Fuhs Mark C. , VanRhoads Shea R. , Casale Amanda E. , McNaughton Bruce , Touretzky David S.
Published: June 2005

To assess the effects of interactions between angular path integration and visual landmarks on the firing of hippocampal neurons, we recorded from CA1 pyramidal cells as rats foraged in two identical boxes with polarizing internal cues. In the same-orientation condition, following an earlier experiment by Skaggs and McNaughton, the boxes were oriented identically and connected by a corridor. In the opposite-orientation condition, the boxes were abutted by rotating them 90° in opposite directions, so that their orientations differed by 180°. After 16–23 days of pretraining on the same-orientation condition, three rats experienced both conditions in counterbalanced order on each of two consecutive days. On the third day they ran two opposite-orientation trials. Although Skaggs and McNaughton observed stable partial “remapping” of place fields, none of the fields in this experiment remapped in the same-orientation condition. In the opposite-orientation condition, place fields in the first box were isomorphic with those in the same-orientation condition, whereas in the second box the rats eventually exhibited completely different fields. The rats differed as to the trial in which this first occurred. Once the second box exhibited different fields, it continued to do so in all subsequent opposite-orientation trials, yet fields remained the same in subsequent same-orientation trials. The results demonstrate that when animals move actively between environments, and are thus potentially able to maintain their inertial angular orientation, discordance between environmental orientation and the rat's idiothetic direction sense can profoundly affect the hippocampal map—either immediately, or as a result of cumulative experience.
Why Do Lipid Transfer Protein-Hypersensitive Patients Tolerate Bean (and Other Legumes)?
Authors: Asero R. , Mistrello G. , Roncarolo D. , Amato S. , Falagiani P.
Published: June 2005

Background: Patients allergic to nonspecific lipid transfer protein (LTP) frequently score positive on SPT with legumes but virtually never report adverse reactions eating these foods. Objective: This study investigated the IgE reactivity to legumes of LTP-allergic patients and aimed to establish whether legumes can be considered safe in LTP-allergic patients. Methods: Skin reactivity as well as clinical allergy to bean and pea were evaluated in a large cohort of LTP-hypersensitive patients. Sera from 12 patients showing clinical allergy to a number of botanically unrelated plant-derived foods and high levels of IgE to peach LTP were employed in in vitro studies (ELISA, ELISA inhibition, SDS-PAGE/immunoblot) aiming to investigate IgE reactivity to bean. Results: Preabsorption of patients’ sera with boiled bean extract did not cause any loss of IgE reactivity to peach LTP (whereas boiled apple totally abolished it). Immunoblot analysis did not show any IgE reactivity to bean proteins at about 10 kDa, and the SDS profile of bean showed little or no staining at 10 kDa. Conclusion: Sera from LTP-allergic patients do not seem to show any IgE reactivity to 10-kDa proteins in bean. Whether this is caused by epitopic differences between Rosaceae and bean LTPs or by the fact that LTP is not expressed in bean remains to be established. This study explains why virtually all LTP-allergic patients tolerate legumes and suggests that these foods should be considered safe for patients sensitized to this protein.
SLC26A6 and SLC26A7 Anion Exchangers Have a Distinct Distribution in Human Kidney
Authors: Kujala Minna , Tienari Jukka , Lohi Hannes , Elomaa Outi , Sariola Hannu , Lehtonen Eero , Kere Juha
Published: June 2005

Background: The anion transporters SLC26A6 (PAT1) and SLC26A7, transporting at least chloride, oxalate, sulfate and bicarbonate, show a distinct expression and function in different mammalian species. They are expressed in kidney, but their exact localization in human kidney has not been studied. We therefore examined SLC26A6 and A7 expression in human kidneys. Methods: The localization of SLC26A6 and A7 in different segments of human nephrons was studied by RT-PCR and immunohistochemistry by comparing to the tubular markers PNRA, CD10, Tamm-Horsfall antigen, high molecular weight cytokeratin, CK7, AQP2 and H+V-ATPase. Results: In human kidney, SLC26A6 is expressed in distal segments of proximal tubules, parts of the thin and thick ascending limbs of Henle’s loops, macula densa, distal convoluted tubules and a subpopulation of intercalated cells of collecting ducts. SLC26A7 is expressed in extraglomerular mesangial cells and a subpopulation of intercalated cells of collecting ducts. Conclusion: Our results show that in human kidney SLC26A6 and A7 have a distinct, partially overlapping expression in distal segments of nephrons. The distribution partly differs from that found previously in rodent kidneys.
Abnormal Cytokine Synthesis as a Consequence of Increased Intracellular Oxidative Stress in Children Treated with Dialysis
Authors: Zachwieja Jacek , Zaniew Marcin , Runowski Dariusz , Lewandowska-Stachowiak Maria , Stefaniak Ewa , Siwińska Aldona
Published: June 2005

Background/Aim: End-stage renal disease (ESRD) induces a clinical state of immunodeficiency with a higher incidence of infections and higher mortality due to infectious complications compared with the normal population. The definite mechanism responsible for the host defense alterations is not well understood. The aim of the study was to investigate intracellularly the relationship between cytokine synthesis and oxidative stress in peripheral blood lymphocytes in children with ESRD. Methods: Twenty-one children (age 11.7 ± 5.8 years) with ESRD treated with hemodialysis (HD; n = 10) and peritoneal dialysis (PD; n = 11) were studied. Nine healthy children of comparable age formed the control group. To determine intracellular oxidative stress we used dihydrorhodamine-123 (DHR), which after oxidation to rhodamine-123 (RHO) emitted a bright fluorescent signal. Intracellular oxidation of DHR in T lymphocytes reflected intracellular oxidative stress. The intracellular synthesis of cytokines (IL-2, IFN-γ, IL-4, IL-6) was also measured. Both parameters were detected at a single-cell level by flow cytometry. Lymphocyte subsets were evaluated using the monoclonal antibodies conjugated with fluorochromes. Results: We found that in T lymphocytes the mean fluorescence intensity (MFI), which reflected intracellular oxidative stress, was increased in ESRD patients compared to the controls (CD3+: 34.77 ± 11.55 vs. 22.55 ± 4.97, p < 0.01; CD3+CD8+: 34.31 ± 12.17 vs. 20.77 ± 4.89, p < 0.01; CD3+CD4+: 36.06 ± 6.98 vs. 24.44 ± 7.68, p < 0.001). HD patients showed slightly higher MFI compared to PD patients in CD3+ cells (39.32 ± 11.70 vs. 30.63 ± 10.20, NS), in CD3+CD8+ cells (37.90 ± 14.32 vs. 31.06 ± 9.34, NS) and in CD3+CD4+ cells (40.10 ± 2.28 vs. 29.33 ± 7.06, p < 0.001). The intracellular synthesis of IL-2 was higher in ESRD patients compared to the controls, both in CD3+ cells (31.34 ± 9.80 vs. 20.49 ± 15.26%, p < 0.05) and in CD3+CD4+ cells (36.10 ± 8.69 vs. 24.03 ± 16.95%, p < 0.05). The intracellular synthesis of IFN-γ, IL-4 and IL-6 was significantly lower in the ESRD group compared to the controls. Interestingly, in patients treated with HD, negative correlations between the degree of intracellular oxidative stress and intracellular cytokine synthesis in CD3+ lymphocytes were found. Conclusion: Our results show that patients with ESRD, especially those treated with HD, present increased oxidative stress in T lymphocytes, which may lead to decreased cytokine synthesis and abnormal immune response.
Is the Effect of Alcohol on Risk of Stroke Confined to Highly Stressed Persons?
Authors: Nielsen N.R. , Truelsen T. , Barefoot J.C. , Johnsen S.P. , Overvad K. , Boysen G. , Schnohr P. , Grønbæk M.
Published: June 2005

Background: Psychological stress and alcohol are both suggested as risk factors for stroke. Further, there appears to be a close relation between stress and alcohol consumption. Several experimental studies have found alcohol consumption to reduce the immediate effects of stress in a laboratory setting. We aimed to examine whether the association between alcohol and stroke depends on level of self-reported stress in a large prospective cohort. Methods: The 5,373 men and 6,723 women participating in the second examination of the Copenhagen City Heart Study in 1981–1983 were asked at baseline about their self-reported level of stress and their weekly alcohol consumption. The participants were followed-up until 31st of December 1997 during which 880 first ever stroke events occurred. Data were analysed by means of Cox regression modelling. Results: At a high stress level, weekly total consumption of 1–14 units of alcohol compared with no consumption seemed associated with a lower risk of stroke (adjusted RR: 0.57, 95% CI: 0.31–1.07). At lower stress levels, no clear associations were observed. Regarding subtypes, self-reported stress appeared only to modify the association between alcohol intake and ischaemic stroke events. Regarding specific types of alcoholic beverages, self-reported stress only modified the associations for intake of beer and wine. Conclusions: This study indicates that the apparent lower risk of stroke associated with moderate alcohol consumption is confined to a group of highly stressed persons. It is suggested that alcohol consumption may play a role in reducing the risk of stroke by modifying the physiological or psychological stress response.
Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts
Authors: Fujita Masashi , Minamino Tetsuo , Asanuma Hiroshi , Sanada Shoji , Hirata Akio , Wakeno Masakatsu , Myoishi Masafumi , Okuda Hiroko , Ogai Akiko , Okada Ken-ichiro , Tsukamoto Osamu , Koyama Hidekazu , Hori Masatsugu , Kitakaze Masafumi
Published: June 2005

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4±3.8 to 19.3±5.2 mL/100 g/min;
P
<0.05), along with decreases in fractional shortening (FS) (8.4±0.7 to 5.4±0.4%;
P
<0.05) and lactate extraction rate (LER) (−31.7±2.9 to −41.4±3.7%;
P
<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.
Urine Albumin Excretion and Subclinical Cardiovascular Disease
Authors: Kramer Holly , Jacobs David R. , Bild Diane , Post Wendy , Saad Mohammed F. , Detrano Robert , Tracy Russell , Cooper Richard , Liu Kiang
Published: June 2005

We examined the association between urine albumin excretion (UAE) and common and internal carotid artery intima-media thickness (IMT), end-diastolic left ventricular (LV) mass, and coronary artery calcification (CAC) scores using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults aged 45 to 85 years without clinical cardiovascular disease (CVD). The mean age of the MESA participants was 62.7 years, 47% were male, and 15% had diabetes mellitus (DM). Sex-specific spot urine albumin/creatinine ratios were used to define 4 UAE categories: normal, high normal, microalbuminuria, and macroalbuminuria. CAC scores were log-transformed after adding 1 to all scores. Mean values of subclinical CVD measures were computed by level of UAE after adjustment for blood pressure, DM, and other covariates. After adjustment for all covariates, geometric mean CAC scores were higher among participants with high normal UAE (8.8;
P
=0.07), microalbuminuria (9.9;
P
=0.002), and macroalbuminuria (13.1;
P
=0.02) compared with normal UAE (7.4), but only microalbuminuria reached statistical significance. Mean LV mass (g/m
2.7
) was significantly higher in participants with high normal UAE (37.0;
P
=0.001), microalbuminuria (38.3;
P
≤0.0001), and macroalbuminuria (42.3;
P
≤0.0001) compared with normal UAE (36.0) after adjustment for all covariates. No significant difference in mean carotid IMT was found after adjustment for all covariates. Similar results were noted in MESA participants with and without DM. In conclusion, higher UAE, including levels below microalbuminuria, may reflect the presence of subclinical CVD among adults without established CVD.
Calcified Rheumatic Valve Neoangiogenesis Is Associated With Vascular Endothelial Growth Factor Expression and Osteoblast-Like Bone Formation
Authors: Rajamannan Nalini M. , Nealis Thomas B. , Subramaniam Malayannan , Pandya Sanjay , Stock Stuart R. , Ignatiev Constatine I. , Sebo Thomas J. , Rosengart Todd K. , Edwards William D. , McCarthy Patrick M. , Bonow Robert O. , Spelsberg Thomas C.
Published: June 2005

Background—

Rheumatic heart disease is the most common cause of valvular disease in developing countries. Despite the high prevalence of this disease, the cellular mechanisms are not well known. We hypothesized that rheumatic valve calcification is associated with an osteoblast bone formation and neoangiogenesis.

Methods and Results—

To test this hypothesis, we examined human rheumatic valves replaced at surgery (n=23), normal human valves (n=20) removed at cardiac transplantation, and degenerative mitral valve leaflets removed during surgical valve repair (n=15). Microcomputed tomography was used to assess mineralization fronts to reconstruct the extents of mineralization. Immunohistochemistry was used to localize osteopontin protein, α-actin, osteocalcin, vascular endothelial growth factor, von Willebrand factor, and CD68 (human macrophage). Microcomputed tomography demonstrated complex calcification developing within the heavily calcified rheumatic valves, not in the degenerative mitral valves and control valves. Immunohistochemistry localized osteopontin and osteocalcin to areas of smooth muscle cells within microvessels and proliferating myofibroblasts. Vascular endothelial growth factor was present in areas of inflammation and colocalized with the CD68 stain primarily in the calcified rheumatic valves. Alizarin red, osteopontin, and osteocalcin protein expression was upregulated in the calcified rheumatic valves and was present at low levels in the degenerative mitral valves.

Conclusions—

These findings support the concept that rheumatic valve calcification is not a random passive process but a regulated, inflammatory cellular process associated with the expression of osteoblast markers and neoangiogenesis.
Noninvasive Imaging of Angiogenesis With a
99m
Tc-Labeled Peptide Targeted at α
v
β
3
Integrin After Murine Hindlimb Ischemia
Authors: Hua Jing , Dobrucki Lawrence W. , Sadeghi Mehran M. , Zhang Jiasheng , Bourke Brian N. , Cavaliere Patti , Song James , Chow Conroy , Jahanshad Neda , van Royen Niels , Buschmann Ivo , Madri Joseph A. , Mendizabal Marivi , Sinusas Albert J.
Published: June 2005

Background—

Noninvasive imaging strategies play a critical role in assessment of the efficacy of angiogenesis therapies. The α
v
β
3
integrin is activated in angiogenic vessels and represents a potential target for noninvasive imaging of angiogenesis.

Methods and Results—

We evaluated a
99m
Tc-labeled peptide (NC100692) targeted at α
v
β
3
integrin for imaging in an established murine model of angiogenesis induced by hindlimb ischemia. Control mice (n=9) or mice with surgical right femoral artery occlusion (n=29) were injected with NC100692 (1.5±0.2 mCi IV) at different times after femoral occlusion (1, 3, 7, and 14 days) for in vivo pinhole planar gamma camera imaging. Tissue from hindlimb proximal and distal to occlusion was excised for gamma well counting and for immunostaining. On in vivo pinhole images, increased focal NC100692 activity was seen distal to the occlusion at days 3 and 7. This increase in relative NC100692 activity was confirmed by gamma well counting. Lectin staining confirmed increased angiogenesis in the ischemic hindlimb at these time points. A fluorescent analogue of NC100692 was used to confirm specificity and localization of the targeted tracer in cultured endothelial cells. In addition, endothelial cell specificity was confirmed on tissue sections with the use of dual immunofluorescent staining of endothelium and the fluorescent analogue targeted at the α
v
β
3
integrin.

Conclusions—

A
99m
Tc-labeled peptide (NC100692) targeted at α
v
β
3
integrin selectively localized to endothelial cells in regions of increased angiogenesis and could be used for noninvasive serial “hot spot” imaging of angiogenesis. This targeted radiotracer imaging approach is a major advance in tracking therapeutic myocardial angiogenesis and has an important clinical potential.
Calcium Concentration of Individual Coronary Calcified Plaques as Measured by Multidetector Row Computed Tomography
Authors: Moselewski Fabian , O’Donnell Christopher J. , Achenbach Stephan , Ferencik Maros , Massaro Joe , Nguyen Ann , Cury Ricardo C. , Abbara Suhny , Jang Ik-Kyung , Brady Thomas J. , Hoffmann Udo
Published: June 2005

Background—

Characteristics of individual calcified plaques, especially calcium concentration (CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and evaluation of therapeutic intervention. In this study, therefore, we assessed the characteristics of individual calcified plaques and their relationship to other parameters derived from CT analysis of coronary calcium in a community-based cross-sectional cohort.

Methods and Results—

Coronary artery calcium (CAC) was analyzed in 612 participants of the Framingham Heart Study (third-generation and offspring cohorts) using prospectively ECG-triggered multidetector CT. We determined the CC, Agatston score, calcified volume, and mineral mass of individual calcified plaques in each subject. Heterogeneity of CC was defined as the standard deviation of CC of all individual calcified plaques in a subject. CAC was detected in 274 of 605 subjects. After excluding 57 subjects (21%) because of motion artifacts, we identified a total of 956 calcified coronary plaques in 217 subjects (74 women, 143 men; mean age, 57.1±10.8 years) with detectable CAC and no image artifacts. CC of individual calcified plaques was independent of subject age (
P
=0.76) and sex (197.8±74.8 versus 183.6±52.8 mg/cm
3
for men versus women;
P
=0.21). Among a subgroup of 125 subjects with multiple (≥3) individual calcified plaques, CC was heterogeneous within individual subjects (mean SD of CC, 43.6±23.1 mg/cm
3
). The degree of heterogeneity of CC in these subjects was independent of age (
P
=0.60), sex (
P
=0.99), and number of plaques (
P
=0.06).

Conclusions—

The CC of individual calcified plaques is independent of age and sex but heterogeneous within a subject, which may reflect that the pathological process of calcified plaque formation and progression is the same in men and women regardless of age. CC may have incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and the evaluation of therapeutic intervention. Further studies are warranted to confirm that individual plaque analysis is preferable to global CAC scores to evaluate progression of atherosclerosis and to assess whether individual plaque analysis may be complementary to global CAC measures to assess coronary event risk.
Thoracic Spinal Cord Stimulation Reduces the Risk of Ischemic Ventricular Arrhythmias in a Postinfarction Heart Failure Canine Model
Authors: Issa Ziad F. , Zhou Xiaohong , Ujhelyi Michael R. , Rosenberger Josh , Bhakta Deepak , Groh William J. , Miller John M. , Zipes Douglas P.
Published: June 2005

Background—

Thoracic spinal cord stimulation (SCS) is a promising therapy in treating refractory angina. This study was designed to investigate SCS with regard to the risk of arrhythmias during myocardial ischemia and its cardiac electrophysiological effects.

Methods and Results—

We studied 22 dogs with healed anterior myocardial infarction (MI) and superimposed heart failure (HF) induced by rapid ventricular pacing. SCS was applied at the dorsal T
1
–T
2
segments of the spinal cord (at 50 Hz, 0.2 ms) for 15 minutes. Transient (2-minute) myocardial ischemia was induced on 2 separate occasions (no SCS and SCS) to provoke ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation; VT/VF). Ischemic episodes were separated by 90 minutes, and dogs were randomly assigned to receive SCS or no SCS before the first or second ischemic episode. SCS reduced the occurrence of VT/VF from 59% to 23% when SCS was applied during transient myocardial ischemia (odds ratio, 0.36; 95% confidence interval, 0.1626 to 0.5646;
P
=0.0009). SCS also decreased sinus rate by 7.5±14 bpm (
P
=0.048), increased the PR interval by 11.1±14.7 ms (
P
=0.009), and reduced systolic blood pressure by 9.8±13.6 mm Hg (
P
=0.02).

Conclusions—

Thoracic SCS appears to protect against ischemic VT/VF in a canine model of healed MI and HF. SCS reduced sinus rate and systolic blood pressure, changes consistent with the previously known antisympathetic effect of SCS, which may have contributed to the antiarrhythmic benefits.
Long-Term, Randomized Comparison of Balloon Angioplasty and Surgery for Native Coarctation of the Aorta in Childhood
Authors: Cowley Collin G. , Orsmond Garth S. , Feola Peter , McQuillan Lon , Shaddy Robert E.
Published: June 2005

Background—

The purpose of this study was to compare the long-term outcomes of children randomized to surgery or balloon angioplasty (BA) for native coarctation (CoA). A prior randomized, short-term comparison of BA and surgery for native CoA in 36 children demonstrated equivalent relief of obstruction. The risk of aneurysm formation and possibly restenosis was higher among patients treated with BA.

Methods and Results—

Blood pressure, residual aortic obstruction, and exercise performance were evaluated. Need for repeat intervention was reviewed. Aortic arch anatomy was assessed with magnetic resonance angiography. For subjects who were not available to return for evaluation, the most recent clinical record was utilized. Among the 36 subjects initially randomized, 21 returned for evaluation (11 BA, 10 surgery). The average time since initial intervention to evaluation for all subjects was 10.6±4.7 years for BA subjects and 11.3±3.7 years for surgical subjects. Resting blood pressure, CoA gradient, exercise performance, MRI analysis of the aortic arch, and need for repeat interventions were not different for the 2 treatment strategies. There was a higher incidence of aneurysm formation (35% versus 0%) and a greater difference in blood pressure between the right and left legs with exercise among BA subjects. Some aneurysms developed late, first being detected more than 5 years after the initial intervention. Only 50% of BA subjects remained free of both aneurysm formation and repeat intervention compared with 87.5% of surgical subjects (
P
=0.03).

Conclusions—

BA for the treatment of childhood CoA is associated with a higher incidence of aneurysm formation and iliofemoral artery injury than surgery. These differences should be considered when undertaking treatment for native CoA during childhood.
Magnitude of and Risk Factors for In-Hospital and Postdischarge Stroke in Patients With Acute Coronary Syndromes
Authors: Budaj Andrzej , Flasinska Katarzyna , Gore Joel M. , Anderson Frederick A. , Dabbous Omar H. , Spencer Frederick A. , Goldberg Robert J. , Fox Keith A.A.
Published: June 2005

Background—

Stroke is a recognized complication after acute myocardial infarction, but few studies have investigated the incidence and outcome of stroke in patients with acute coronary syndrome (ACS). This study examined the incidence and outcomes of hemorrhagic and nonhemorrhagic stroke and risk factors associated with stroke in patients with ACS.

Methods and Results—

Data were obtained from 35 233 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) with an ACS. In-hospital strokes occurred in 310 patients (0.9%), of which 100 (32.6%) were fatal. The incidence of in-hospital stroke was significantly higher in patients with ST-segment–elevation myocardial infarction than in non–ST-segment myocardial infarction or unstable angina (1.3%, 0.9%, 0.5%, respectively;
P
<0.001). Overall, 35.5% of in-hospital strokes occurred within 6 days of hospitalization. The strongest risk factor for in-hospital nonhemorrhagic stroke was in-hospital CABG, followed by in-hospital atrial fibrillation, previous stroke, initial enzyme elevation, and advanced age. Prior statin use was a protective factor. After controlling for potential confounders, in-hospital mortality was significantly higher among patients who experienced an in-hospital stroke (adjusted odds ratio, 8.3; 95% CI, 6.0 to 11.4). A total of 269 additional strokes (1.1%) occurred within 6 months after discharge from hospital, of which 56 (20.9%) were fatal. The most important risk factor for postdischarge stroke was the occurrence of an in-hospital stroke.

Conclusions—

Stroke is an uncommon event in patients with ACS but is associated with high mortality. Despite current therapy, the incidence of postdischarge stroke is not low. New approaches are warranted to reduce the risk of stroke in patients with ACS.