bluuebunny/crossref_metadata_2025 huggingface dataset:
Content of Kynurenic Acid and Activity of Kynurenine Aminotransferases in Mammalian Eyes
Authors: Zarnowski Tomasz , Rejdak Robert , Zagorski Zbigniew , Juenemann Anselm G.M. , Zrenner Eberhart , Kocki Tomasz , Urbanska Ewa M. , Turski Waldemar A.
Published: March 2004

The present study investigated the kynurenic acid (KYNA) contents and kynurenine aminotransferase (KAT I and II) activity in structures of the human, monkey, rabbit and bovine eye. KYNA levels were investigated with HPLC and detected fluorimetrically. The activity of KAT I and II was assayed as quantitative analysis of newly synthesized KYNA in vitro. Mean KYNA levels (±SD) in the human retina and vitreous body were 36.8 ± 7.6 and 33.1 ± 6.2 pmol/g wet tissue weight, respectively. In human eyes, KAT I activity in the vitreous body was 0.57 ± 0.28, that of KAT II was 2.56 ± 0.69. KAT I activity in the retina was 3.42 ± 1.17 and that of KAT II 10.75 ± 9.2. (KAT activity is expressed as KYNA synthesis in picomoles per gram wet tissue weight per hour.) The values of KYNA and KAT observed in other mammalian species tested were in the same range. In conclusion, KYNA and KAT enzymatic activity are present in the structures of human and other mammalian eyes.
Complexity in Health Care Systems
Authors: Penchas Shmuel
Published: March 2004

Health care systems are complex systems with many independent agents each interacting with the others, occasionally inducing changes in some, and creating complex adaptive systems containing emergent property potential. Amongst the independent agents in health care systems there are language, structure, logic and social order. Each is fraught with fundamental problems, leading to famous paradoxes. Some of these parameters are initial conditions in complex adaptive systems, which can but do not have to be sensitive to changes in initial conditions – leading to future significant effects. It is still impossible to predict the appearance of emergent properties from independent agent behavior, and evolving health care systems can thus become undesirable and fail. Much of all this applies to other social systems. However, there are systems with foreseeable behavior – uniform, repetitive and nested ones. These are simple systems, with reducible computations for predicting their future development. In health care systems, one needs to reduce unpredictable developmental failure by emulating such simple systems through the implementation of their basic qualities.
Effect of Epidermal Growth Factor on the Developing Rat Renal Papilla
Authors: Lee Seung-Hun , Jung Ju-Young , Han Ki-Hwan , Yang Chul-Woo , Choi Kyu-Bok , Kim Jin
Published: March 2004

Background: Apoptosis plays an important role in the morphogenesis of the renal papilla. During kidney development, ATL is derived from the TAL in the inner medulla by apoptotic deletion of a fraction of TAL cells and the transformation of the remaining TAL cells. EGF is an important regulator of apoptosis in the kidney. Hypothesis: Exogenously administered EGF in postnatal rat affects renal papilla growth with cell proliferation and apoptosis in the loop of Henle. Methods: Rat pups received subcutaneous injections of EGF (0.3 µg/g body weight) or saline four times a day from after birth. Rats were sacrificed and the kidneys were preserved for immunohistochemistry on day 4 and day 7. The TAL was identified with antibody directed against Na-K-ATPase or BSC1, and type A intercalated cells were identified with antibody to anion exchanger 1 (AE1). Apoptosis was detected with TUNEL method, and cell proliferation with immunostaining for PCNA. Results – Primary and Secondary: EGF treatment resulted in the following: (1) reduced kidney weight; (2) shortened length of renal papilla; (3) delayed transformation of the cuboidal epithelium into the squamous epithelium of the ATL; (4) delayed elimination of type A intercalated cells in the medullary collecting duct; (5) decreased both apoptotic index and PCNA-positive cells in the TAL and the collecting duct of the renal medulla. Conclusion: These findings suggest that exogenous EGF delays the development of loop of Henle in the renal papilla by reducing both apoptosis and cell proliferation.
Is the Use of Selective COX Inhibitors Associated with an Increased Risk of Cardiovascular Events?
Authors: Otterstad Jan Erik
Published: March 2004

The assumption that long-term treatment with rofecoxib is associated with an increased cardiovascular risk when compared with naproxen is based upon a small number of events in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study. That study, however, was not designed to assess adverse cardiovascular events. A review of the available literature does not support such an assumption. Further studies designed to elucidate whether treatment with cyclooxygenase 2 (COX-2) inhibitors is associated with an increased cardiovascular risk are needed. In patients with a high cardiovascular risk, treatment with COX-2 inhibitors should be combined with aspirin, while the combination of a conventional nonsteroidal anti-inflammatory drug and aspirin ought to be avoided due to an increased risk of adverse gastrointestinal effects.
Congenital Oral Mucosal Abnormalities in True Umbilical Cord Knots
Authors: De Felice Claudio , Bianciardi Giorgio , Parrini Stefano , Laurini Ricardo N. , Latini Giuseppe
Published: March 2004

Objective: The pathogenesis and clinical significance of true umbilical cord knots remain controversial. Here, we tested the hypothesis of the presence of congenital oral mucosal changes in newborns with true umbilical cord knots. Study design: Seven consecutive infants with true umbilical cord knots and 50 gestational age- and sex-matched controls were enrolled. The proportion of oral frenulum abnormalities and the two-dimensional vascular network geometry [fractal dimension, D, at two scales: D(1–46), and D(1–15), with the relative Lempel-Ziv complexity, (L-Z)], were analyzed. Results: Infants with true umbilical cord knots showed significantly higher proportions of mandibular frenulum agenesis compared to controls (p = 0.000006). The oral vascular networks of these infants exhibited a significantly higher D(1–46) and D(1–15) (p < 0.0001, respectively), and higher L-Z values (p < 0.0001) than control networks. Conclusion: These findings indicate the presence of significant congenital oral mucosal changes in newborn infants with true umbilical cord knots, thus suggesting a previously unrecognized association between true umbilical cord knots and a subclinical extracellular matrix disorder.
Surgery for Hilar Cholangiocarcinoma: Feasibility and Results of Parenchyma-Conserving Liver Resection
Authors: Ramesh Hariharan , Kuruvilla Kuruvilla , Venugopal Ambadi , Lekha Vijayalakshmi , Jacob George
Published: March 2004

Background/Aim: Major liver resection has improved the resectability rate of hilar cholangiocarcinomas, but morbidity and mortality may be significant. The aim of this study was to assess the value of parenchyma-conserving liver resection (resection of bile duct with liver segments I and IVb; PCLR) in hilar cholangiocarcinoma. Methods: Retrospective analysis of prospectively collected data. Factors influencing survival following three types of operations were studied by univariate and multivariate analyses. The three types of operations were: (1) local resection of the bile duct alone (LR); (2) major liver resection (resection of three or more segments, hepatic resection; HR), and (3) PCLR. Results: Forty-six patients (21 males, 25 females; age range 35–77 years, mean age 57, median age 57 years) underwent surgery. There were 11 LR, 12 HR, and 23 PCLR procedures. There were 3 deaths (mortality 6.5%). The mortality was higher following HR (3 out of 12; 25%) than following LR or PCLR (0 out of 34; p = 0.01). Survival was longer following curative resection (median 27 months) than after palliative resection (median 15 months; p = 0.001). Lymph nodal and perineural involvement were adverse factors on univariate, but not on multivariate analysis. PCLR produced better survival (median 29 months) as compared with LR (median 15 months) or HR (median 22.5 months; p < 0.01). Conclusions: PCLR is applicable to selected patients with Bismuth-Corlette type III disease without major vascular involvement and produces survival rates comparable to those of LR and HR. PCLR may help avoid major liver resections in some patients with hilar cholangiocarcinoma.
Genetic Predisposition to Neurological Symptoms in Lacunar Infarction
Authors: Zhang Jun-hui , Kohara Katsuhiko , Yamamoto Yasumasa , Nakura Jun , Tabara Yasuharu , Fujisawa Mutsuo , Katagi Ryosuke , Miki Tetsuro
Published: March 2004

Objective: Lacunar infarction is a unique stroke entity with characteristic symptoms. However, it is often silent clinically. The possible genetic predisposition to symptoms of lacunar infarction was investigated. Methods: One-hundred and fifty-one patients with lacunar stroke were consecutively recruited. Lacunar stroke was diagnosed based on both neurological symptoms and lacunar lesion(s), demonstrated by MRI, that were responsible for the symptoms. One-hundred and fifty control subjects with MRI-proven lacunar lesions without neurological symptoms served as controls. There was no significant difference in age, sex and prevalence of known risk factors between cases and controls. Insertion and deletion polymorphisms of the angiotensin-converting enzyme gene (ACE), M235T substitution of the angiotensinogen gene (AGT), and A1133C substitution of type 1 receptor of the angiotensin II gene were determined. Results: The frequency of ACE D allele was significantly higher in symptomatic patients compared with asymptomatic subjects (0.44 vs. 0.36, p < 0.05). The genotype distribution of AGT was significantly different between symptomatic and asymptomatic patients (χ2 = 6.6, p = 0.037). Multiple logistic regression analysis revealed that ACE gene and AGT genotypes were independently associated with the neurological manifestation of lacunar infarction. In subjects with 1 lacuna, the odds ratio of the ACE DD genotype for symptomatic manifestation was 4.98 (95% CI 1.25–19.9). In subjects with 4 or more lacunae, the odds ratio of the ACE II genotype for symptomatic manifestation was 0.24 (95% CI 0.10–0.56). Furthermore, the ACE gene polymorphism was significantly different between symptomatic patients with a single lacuna and asymptomatic subjects with 4 or more multiple lacunar infarctions (χ2 = 10.6, p = 0.005). Conclusion: These findings suggest that 2 subtypes of lacunar infarction, single symptomatic lacuna and multiple asymptomatic lacunae, may possess different genetic backgrounds. Subjects with the ACE DD genotype could be more predisposed to be symptomatic in first-ever lacunar stroke, while the ACE II genotype may convey resistance to symptoms even after multiple lacunar strokes. Polymorphism of genes of the renin-angiotensin system could be involved in the manifestation of neurological symptoms of lacunar infarction.
Georg Friedrich Händel’s Strokes
Authors: Bäzner H. , Hennerici M.
Published: March 2004

Georg Friedrich Händel was a musical giant and probably the first composer to be the manager and promoter of his own works. The story of his life and illnesses is full of myths, invented and embellished by various biographies. Existing pathographies written by authors from various specialities suggested he suffered from psychiatric diseases like cyclothymia or mania and rheumatologic disorders like arthritis, while others tended to interpret his recurrent palsies as typical sequelae of ischemic strokes. During the last years of life, Händel was struck with blindness, which in his era was interpreted as being due to cataracts. This led to three ‘coucher’ operations, all of them without lasting effect. Although a definite diagnosis cannot be inferred from the original sources, the most plausible explanation for Händel’s palsies and visual impairment may be cerebrovascular disease. The possible differential diagnosis will be discussed in this paper.
The Basophil-Specific Ectoenzyme E-NPP3 (CD203c) as a Marker for Cell Activation and Allergy Diagnosis
Authors: Bühring Hans-Jörg , Streble Anna , Valent Peter
Published: March 2004

Basophils are effector cells of allergic reactions. These cells produce and store a number of vasoactive and immunomodulatory mediators. During an allergic reaction, basophils can release their mediator substances into the extracellular space and thus contribute to the clinical picture and symptoms in allergy. The phenotypic hallmark of basophils is expression of high-affinity IgE receptors (FcΕRI) on their cell surface together with expression of the activation-linked molecule CD203c. This ectoenzyme is located both on the plasma membrane and in the cytoplasmic compartment of basophils. Cross-linking of the FcΕRI by an allergen or anti-IgE antibody results in a rapid upregulation of intracellular CD203c molecules to the cell surface and is accompanied by mediator release. CD203c is therefore a promising target molecule for a flow cytometry-based test to analyze sensitized individuals and patients with type I allergy. In the present article, we review the current knowledge of CD203c with special regard to its tissue distribution and regulation in basophil activation. In addition, we discuss the application of CD203c in allergy diagnosis.
Expression of Actin and Tubulins in Purified Human Basophil Leukocytes upon Stimulation with IL-3
Authors: Nielsen Henrik Vendelbo , Johnsen Anders H. , Schiøtz P.O.
Published: March 2004

Background: Pharmacological and morphological results indicate that the cytoskeleton proteins tubulins and actin play a role in the histamine release process in basophil leukocytes and mast cells. In this report, we investigate the expression of these cytoskeleton proteins in purified human basophils upon stimulation with anti-IgE and IL-3. Methods: Human basophils were purified using a negative selection procedure. They were incubated for 6 h with anti-IgE and/or IL-3 in radiolabeling media. Proteins in the cells were analyzed by two-dimensional gel electrophoresis and autoradiography. Actin and α- and β-tubulin were identified by amino acid sequence analysis or matrix assisted laser desorption/ionisation time-of-flight mass spectrometry. The synthesis of these proteins under different experimental conditions was evaluated by densitometry. Results: Actin is regulated dose dependently by IL-3 with an optimum concentration of 100 ng/ml, corresponding to the optimal IL-3 concentration for enhancement of histamine release. The synthesis of tubulins was not significantly upregulated by IL-3 or anti-IgE alone, but there was a slight and significant upregulation of tubulins upon stimulation with both IL-3 and anti-IgE in doses optimal for maximal histamine release. Conclusions: The de novo synthesis of actin is regulated dose dependently by IL-3 in purified human basophils in short-term culture. The optimum IL-3 concentration is the same as for enhancement of histamine release, suggesting that the same processes that regulate IL-3-induced enhancement of histamine release also regulate the expression of actin. The finding that the expression of the tubulins is not upregulated by IL-3 alone suggests that regulation of tubulin synthesis is not a pathway by which IL-3 in itself primes basophil histamine release.
Caspase-3-Mediated Apoptosis of Human Eosinophils by the Tissue-Invading Helminth Paragonimus westermani
Authors: Min Duk-Young , Lee Young-Ah , Ryu Jae-Sook , Ahn Myung-Hee , Chung Young-Bae , Sim Seobo , Shin Myeong Heon
Published: March 2004

Background: Eosinophils are important cells in host immunity to infections by parasitic worms. Tissue-invasive helminthic parasites have been known to induce apoptosis of immune cells for their successful establishment in vivo. We have previously found that high doses of excretory-secreted products (ESP) secreted by lung fluke Paragonimus westermani newly excysted metacercariae (PwNEM), which cause pulmonary or extrapulmonary paragonimiasis in human beings, accelerate eosinophil cell death. However, little is known about the mechanism of eosinophil apoptosis induced by the Paragonimus-derived products. Objective: We examined involvement of caspase 3 activation in eosinophil cell death induced by ESP produced by PwNEM. Methods: Eosinophils were isolated from the peripheral blood of healthy donors by CD16-negative immunomagnetic selection. We examined the inhibitory effect of pan-caspase inhibitor on ESP-triggered phosphatidylserine (PS) externalization on the outer surface of eosinophils and intracellular activation of caspase 3 in cell lysates treated with the ESP. Results: When ESP secreted by PwNEM were incubated for up to 3 h with eosinophils, they increased surface exposure of PS on eosinophils in a time- and dose-dependent manner. This proapoptotic effect of the ESP on eosinophils was significantly inhibited by pretreatment of cells with pan-caspase inhibitor z-VAD-fmk, and was completely abolished by heat inactivation of ESP at 56°C. The activated forms of caspase 3 were also clearly detected in eosinophils incubated with ESP. Moreover, ESP potently inhibited prolonged survival of eosinophils induced by cytokines such as IL-5, IL-3, and GM-CSF. Conclusion: These results suggest that ESP secreted by PwNEM contain biological active factors causing caspase-3-mediated apoptosis of human eosinophils, thereby enabling the larvae to evade and to subvert the tackle by eosinophils during the early phase of the infection.
Exposure to Indoor Allergens in Homes of Patients with Asthma and/or Rhinitis in Southeast Brazil: Effect of Mattress and Pillow Covers on Mite Allergen Levels
Authors: Tobias Kátia R.C. , Ferriani Virginia P.L. , Chapman Martin D. , Arruda L. Karla
Published: March 2004

Background: Exposure and sensitization to indoor allergens have been associated with the development of asthma and other allergic diseases in many parts of the world. It is important to establish the degree of exposure, and to evaluate whether allergen control measures are effective in a particular area. Methods: Concentrations of major allergens of mites, cockroach, cat and dog were measured in dust samples from homes of 24 mite-allergic patients living in Ribeirão Preto, Brazil. Allergen concentrations were quantitated by monoclonal antibody-based ELISA. Mite-impermeable mattress and pillow covers were applied to beds in the homes of 19 of the 24 patients, and group 1 mite allergen levels were measured 1 and 6 months following intervention. Results: Patients were exposed to high concentrations of mite allergens in their homes. 87.5% of the homes presented concentrations of group 1 allergens >10 µg/g of dust in at least one site. Cockroach allergen concentrations were low in most samples. Dog allergen concentrations were significantly higher in homes with dogs as compared to those without dogs. Mean concentrations of cat allergen were 0.1 µg/g. Mite allergen concentrations in bedding samples dropped from 24 µg/g at baseline to 0.9 and 1.0 µg/g, respectively, 1 and 6 months following encasement of mattresses and pillows. Conclusions: Significant mite allergen reduction can be achieved in an area of high degree of exposure to mite allergens. Further studies evaluating the effect of this reduction on symptoms and airway inflammation will be necessary to establish the effectiveness of mite avoidance measures in our area.
Role of Substance P in an NC/Nga Mouse Model of Atopic Dermatitis-Like Disease
Authors: Ohmura Tsuyoshi , Tsunenari Ichiro , Hayashi Toshihiro , Satoh Yayoi , Konomi Ayako , Nanri Hirotoshi , Kawachi Mamoru , Morikawa Makoto , Kadota Toshihito , Satoh Hisashi
Published: March 2004

Background: Atopic dermatitis (AD) can be exacerbated or induced in genetically predisposed individuals by psychological stress, which causes the release of substance P (SP). Therefore, SP may play an etiological role in the mechanisms underlying AD. Methods: Changes in the number of mast cells and SP-containing mast cells in lesional skin, and the serum concentrations of SP and IgE during the development of AD-like disease up to 8 weeks after the start of picryl chloride (PiCl) induction in NC/Nga mice were examined. Results: Clinical signs and symptoms seen in PiCl-treated NC/Nga mice as a model of AD-like disease began with erythema and haemorrhage, followed by oedema, superficial erosion, deep excoriation, scaling and dryness of the skin, as well as retarded growth, and the changes were exacerbated with an increase in the number of PiCl applications. An increase in the number of mast cells and eosinophil infiltration was observed in the lesional skin. The increase in SP-positive mast cells in the dermis in this model was significant from 1 week after the start of induction treatment, compared with intact mice, and SP-positive nerve fibres were observed in the dermis. Conclusion: SP is a crucial mediator of both dermatitis and scratching behaviour in this model.
Anti-Dysrhythmic Effects of Long-Pulse Gastric Electrical Stimulation in Dogs
Authors: Xu Xiaohong , Qian Liwei , Chen J.D.Z.
Published: March 2004

Background/Aim: The aim of this study was to investigate the anti-dysrhythmic effect of long-pulse gastric electrical stimulation (GES) in dogs. Methods: The study was performed in 7 healthy dogs implanted with 4 pairs of serosal gastric electrodes. Each dog was studied in three sessions on 3 separate days in a randomized order with recordings of gastric slow waves. In session 1 or 2, infusion of either saline or glucagon (0.1 U/kg in 20 ml saline instilled in 40 min) was given during the 2nd and 3rd 20-min periods. The protocol of session 3 was the same as that of session 2 except that GES was performed during the 2nd 20-min period. Results: (1) Glucagon induced gastric dysrhythmia and decreased gastric slow-wave coupling (ANOVA, p < 0.001). The long-pulse GES normalized glucagon-induced gastric dysrhythmia and the uncoupling of slow waves. (2) Glucagon induced symptoms and behaviors suggestive of nausea and the symptoms were not improved by long-pulse GES. Conclusion: (1) Glucagon induces gastric dysrhythmias, slow-wave uncoupling and symptoms, and (2) long-pulse GES normalizes glucagon-induced gastric dysrhythmia and slow-wave uncoupling with no improvement in symptoms.
The Wagner-Nelson Method Can Generate an Accurate Gastric Emptying Flow Curve from 13CO2 Data Obtained by a 13C-Labeled Substrate Breath Test
Authors: Sanaka Masaki , Yamamoto Takatsugu , Ishii Tarou , Kuyama Yasushi
Published: March 2004

Background: In pharmacokinetics, the Wagner-Nelson (W-N) method can accurately estimate the rate of drug absorption from its urinary elimination rate. A stable isotope (13C) breath test attempts to estimate the rate of absorption of 13C, as an index of gastric emptying rate, from the rate of pulmonary elimination of 13CO2. The time-gastric emptying curve determined by the breath test is quite different from that determined by scintigraphy or ultrasonography. In this report, we have shown that the W-N method can adjust the difference. Methods: The W-N equation to estimate gastric emptying from breath data is as follows: the fractional cumulative amount of gastric contents emptied by time t = Abreath(t)/Abreath(∞) + (1/0.65)·d[Abreath(t)/Abreath(∞)]/dt, where Abreath(t) = the cumulative recovery of 13CO2 in breath by time t and Abreath(∞) = the ultimate cumulative 13CO2 recovery. The emptying flow curve generated by ultrasonography was compared with that generated by the W-N method-adjusted breath test in 6 volunteers. Results: The emptying curves by the W-N method were almost identical to those by ultrasound. Conclusions: The W-N method can generate an accurate emptying flow curve from 13CO2 data, and it can adjust the difference between ultrasonography and the breath test.
Human PRMT5 Expression Is Enhanced during in vitro Tubule Formation and after in vivo Ischemic Injury in Renal Epithelial Cells
Authors: Braun Michael C. , Kelly Caitlin N. , Prada Anne E. , Mishra Jaya , Chand Deepa , Devarajan Prasad , Zahedi Kamyar
Published: March 2004

Background: The interactions between cells and the extracellular matrix (ECM) are important in the regulation of cell growth and differentiation. Cells cultured in ECM differentiate and develop tubular structures. The kidney has the ability to partially recover function after an ischemic insult through repairing its tubular epithelium. The factors that contribute to tubule formation in vitro may mediate tubule regeneration in the recovery stage of acute tubular necrosis. Methods: RNA purified from cells grown on plastic, on Matrigel and in Matrigel matrix were subjected to differential display analysis to identify the transcripts that are differentially expressed during in vitro tubulogenesis. Results: Protein arginine methyltransferase 5 (PRMT5) expression increased in renal epithelial cells undergoing tubule formation. PRMT5 expression is developmentally regulated and ubiquitously expressed in a variety of adult tissues. We also demonstrated that expression of PRMT5 is enhanced in the renal tubular epithelium of animals subjected to ischemic reperfusion injury (IRI). Conclusion: The role of PRMT5 in the regulation of mitosis, its induction in renal epithelial cells undergoing tubule formation in vitro and its expression in the tubules of the kidneys subjected to IRI suggest that it functions in the regulation of cell growth and differentiation during tubule formation and regeneration.
Influence of Genetic Polymorphisms of the Renin-Angiotensin System on IgA Nephropathy
Authors: Bantis C. , Ivens K. , Kreusser W. , Koch M. , Klein-Vehne N. , Grabensee B. , Heering P.
Published: March 2004

Background: We evaluated the impact of the three major genetic polymorphisms of the renin-angiotensin system [angiotensinogen (AGT) gene M235T, angiotensin-converting enzyme (ACE) gene-I/D and angiotensin II-type 1 receptor (AT1R) gene A1166C polymorphisms] as risk factors in IgA nephropathy. Methods: The clinical course of 107 patients with biopsy proven IgA nephropathy followed up for 6.6 ± 5.8 years was examined. The genetic polymorphisms were determined by PCR amplification. Results: The allele frequencies of the polymorphisms studied were similar in patients and control subjects. AGT-M235T genotype was associated with the presence of nephrotic syndrome (p < 0.05), correlated to the number of antihypertensive drugs agents taken (p < 0.01) and influenced the rate of deterioration of renal function (p < 0.05). Combined analysis of AGT-M235T and ACE-I/D polymorphisms detected an interaction on affecting progression (p < 0.05). ACE-inhibition had a more pronounced effect in certain AGT-M235T and ACE-I/D genotypes (p < 0.05) and their combined analysis showed a synergistic effect (p < 0.01). No association between AT1R-A1166C polymorphism and any of the parameters studied was observed. Conclusions: Our results suggest that angiotensinogen-M235T polymorphism is an important marker of progression in IgA nephropathy in Caucasian patients, especially when analyzed in combination with ACE-I/D polymorphism.
gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension
Authors: Jung O. , Schreiber J.G. , Geiger H. , Pedrazzini T. , Busse R. , Brandes R.P.
Published: March 2004

Background—

Isoforms of the NADPH oxidase contribute to vascular superoxide anion ( · O
2
−
) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O
2
−
to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction.

Methods and Results—

Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox
−/−
) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox
−/−
mice (158±2 versus 149±2 mm Hg;
P
<0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox
−/−
mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox
−/−
mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox
−/−
mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice.

Conclusions—

These data indicate that the formation of O
2
−
by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.
Taurine Supplementation Reduces Oxidative Stress and Improves Cardiovascular Function in an Iron-Overload Murine Model
Authors: Oudit Gavin Y. , Trivieri Maria G. , Khaper Neelam , Husain Taneya , Wilson Greg J. , Liu Peter , Sole Michael J. , Backx Peter H.
Published: March 2004

Background—

Iron overload has an increasing worldwide prevalence and is associated with significant cardiovascular morbidity and mortality. Elevated iron levels in the myocardium lead to impaired systolic and diastolic function and elevated oxidative stress. Taurine accounts for 25% to 50% of the amino acid pool in myocardium, possesses antioxidant properties, and can inhibit L-type Ca
2+
channels. Thus, we hypothesized that this agent would reduce the cardiovascular effects of iron overload.

Methods and Results—

Iron-overloaded mice were generated by intraperitoneal injection of iron either chronically (5 days per week for 13 weeks) or subacutely (5 days per week for 4 weeks). Iron overload causes increased mortality, elevated oxidative stress, systolic and diastolic dysfunction, hypotension, and bradycardia. Taurine supplementation increased myocardial taurine levels by 45% and led to reductions in mortality and improved cardiac function, heart rate, and blood pressure in iron-overloaded mice. Histological examination of the myocardium revealed reduced apoptosis and interstitial fibrosis in iron-overloaded mice supplemented with taurine. Taurine mediated reduced oxidative stress in iron-overloaded mice along with attenuation of myocardial lipid peroxidation and protection of reduced glutathione level.

Conclusions—

These results demonstrate that treatment with taurine reduces iron-mediated myocardial oxidative stress, preserves cardiovascular function, and improves survival in iron-overloaded mice. The role of taurine in protecting reduced glutathione levels provides an important mechanism by which oxidative stress–induced myocardial damage can be curtailed. Taurine, as a dietary supplement, represents a potential new therapeutic agent to reduce the cardiovascular burden from iron-overload conditions.
A Walnut Diet Improves Endothelial Function in Hypercholesterolemic Subjects
Authors: Ros Emilio , Núñez Isabel , Pérez-Heras Ana , Serra Mercè , Gilabert Rosa , Casals Elena , Deulofeu Ramón
Published: March 2004

Background—

Epidemiological studies suggest that nut intake decreases coronary artery disease (CAD) risk. Nuts have a cholesterol-lowering effect that partly explains this benefit. Endothelial dysfunction is associated with CAD and its risk factors and is reversed by antioxidants and marine n-3 fatty acids. Walnuts are a rich source of both antioxidants and α-linolenic acid, a plant n-3 fatty acid.

Methods and Results—

To test the hypothesis that walnut intake will reverse endothelial dysfunction, we randomized in a crossover design 21 hypercholesterolemic men and women to a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced ≈32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. After each intervention, we obtained fasting blood and performed ultrasound measurements of brachial artery vasomotor function. Eighteen subjects completing the protocol had suitable ultrasound studies. Compared with the Mediterranean diet, the walnut diet improved endothelium-dependent vasodilation and reduced levels of vascular cell adhesion molecule-1 (
P
<0.05 for both). Endothelium-independent vasodilation and levels of intercellular adhesion molecule-1, C-reactive protein, homocysteine, and oxidation biomarkers were similar after each diet. The walnut diet significantly reduced total cholesterol (−4.4±7.4%) and LDL cholesterol (−6.4±10.0%) (
P
<0.05 for both). Cholesterol reductions correlated with increases of both dietary α-linolenic acid and LDL γ-tocopherol content, and changes of endothelium-dependent vasodilation correlated with those of cholesterol-to-HDL ratios (
P
<0.05 for all).

Conclusions—

Substituting walnuts for monounsaturated fat in a Mediterranean diet improves endothelium-dependent vasodilation in hypercholesterolemic subjects. This finding might explain the cardioprotective effect of nut intake beyond cholesterol lowering.
Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis
Authors: Booth A.D. , Jayne D.R.W. , Kharbanda R.K. , McEniery C.M. , Mackenzie I.S. , Brown J. , Wilkinson I.B.
Published: March 2004

Background—

Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti–neutrophil cytoplasmic antibody–associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti–tumor necrosis factor-α (TNF-α) therapy.

Methods and Results—

Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α. The effects of anti–TNF-α therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11±1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8±10.5 versus 1.6±0.2 pg/mL,
P
<0.001; 9.0±0.7 versus 6.7±0.6 pg/mL,
P
=0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects (
P
=0.002), but sodium nitroprusside (SNP) responses were not (
P
=0.3). The response to ACh improved with infliximab treatment (
P
=0.004) in particular, with infliximab alone (
P
=0.03).

Conclusions—

AASV is associated with endothelial dysfunction. Anti–TNF-α therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.
Nitric Oxide and Cardiac Muscarinic Control in Humans
Authors: Chowdhary Saqib , Marsh Anna M. , Coote John H. , Townend Jonathan N.
Published: March 2004

Cardiac parasympathetic activity reduces susceptibility to potentially lethal ventricular arrhythmias in heart failure and ischemic heart disease. This influence is mediated in large part by antagonism of the adverse cardiac effects of sympathetic overactivity (“indirect” parasympathetic activity) in addition to the “direct” effects of muscarinic stimulation. Nitric oxide modulates parasympathetic cardiac signaling in some animal models, but human data are lacking. We have investigated the influence of endogenous nitric oxide on cardiac responses to parasympathetic stimulation in healthy humans. In 18 volunteers, we studied chronotropic and inotropic responses to muscarinic stimulation, both before and after prestimulation with isoproterenol. Cardiac muscarinic stimulation was achieved using an intravenous bolus of the short-acting cholinesterase inhibitor, edrophonium. Responses were assessed during a background infusion of a nitric oxide synthase inhibitor (
N
G
-monomethyl-
l
-arginine [
l
-NMMA]), placebo (saline), or phenylephrine (vasoconstrictor control) in a single-blind, random order, crossover protocol.
l
-NMMA did not affect chronotropic responses to edrophonium alone (direct parasympathetic activity). The decrease in heart rate attributable to “indirect” parasympathetic activity (derived by comparison with the effect of edrophonium during concurrent adrenergic stimulation) was substantially attenuated by
l
-NMMA in comparison to both control infusions. No modification of muscarinic inotropic responses by
l
-NMMA was apparent in comparison to the vasoconstrictor control. Nitric oxide exerts a powerful facilitating influence on indirect (antiadrenergic) but not direct human cardiac parasympathetic control. Stimulation of the endogenous nitric oxide pathway might enhance parasympathetic protection against the adverse influences of cardiac sympathetic overactivity.
Prevalence, Detection, Management, and Control of Hypertension in Ashanti, West Africa
Authors: Cappuccio Francesco P. , Micah Frank B. , Emmett Lynsey , Kerry Sally M. , Antwi Samson , Martin-Peprah Ruby , Phillips Richard O. , Plange-Rhule Jacob , Eastwood John B.
Published: March 2004

Hypertension and stroke are important threats to the health of adults in sub-Saharan Africa. Nevertheless, detection of hypertension is haphazard and stroke prevention targets are currently unattainable. Prevalence, detection, management, and control of hypertension were assessed in 1013 men (n=385) and women (n=628), both aged 55 [SD 11] years, living in 12 villages in Ashanti, Ghana. Five hundred thirty two lived in semi-urban and 481 in rural villages. The participants underwent measurements of height, weight, and blood pressure (BP) and answered a detailed questionnaire. Hypertension was defined as BP ≥140 and/or ≥90 mm Hg or being on drug therapy. Women were heavier than men. Participants in semi-urban areas were heavier and had higher BP (129/76 [26/14] versus 121/72 [25/13] mm Hg;
P
<0.001 for both) than in rural areas. Prevalence of hypertension was 28.7% overall and comparable in men and women, but higher in semi-urban villages (32.9% [95% CI 28.9 to 37.1] versus 24.1% [20.4 to 28.2]), and increased with age. Detection rate was lower in men than women (13.9% versus 27.3%;
P
=0.007). Treatment and control rates were low in both groups (7.8% and 4.4% versus 13.6% and 1.7%). Detection, treatment, and control rates were higher in semi-urban (25.7%, 14.3%, and 3.4%) than in rural villages (16.4%, 6.9%, and 1.7%). Hypertension is common in adults in central Ghana, particularly in urban areas. Detection rates are suboptimal in both men and women, especially in rural areas. Adequate treatment of high BP is at a very low level. There is an urgent need for preventive strategies on hypertension control in Ghana.
Symptomatic and Asymptomatic Retinal Embolism Have Different Mechanisms
Authors: Wijman Christine A.C. , Gomes Joao A. , Winter Michael R. , Koleini Behrooz , Matjucha Ippolit C.A. , Pochay Val E. , Babikian Viken L.
Published: March 2004

Purpose—

To investigate differences between symptomatic and asymptomatic retinal embolism regarding the frequency and source of cerebral microemboli.

Methods—

Thirty-seven patients with transient monocular blindness or retinal infarction and 27 patients (29 eyes) with asymptomatic retinal embolism were prospectively enrolled. Patients underwent a transcranial Doppler study and noninvasive imaging of the cervical internal carotid arteries (ICA). The middle cerebral artery (MCA) ipsilateral to the affected eye was monitored for 30 minutes for microembolic signals (MES), which were saved and analyzed offline. Age-matched controls (n=15) had no history of retinal or brain ischemia, <50% ICA stenosis, and normal ophthalmologic examinations.

Results—

MES were detected in 0/15 (0%) controls, 11/37 (30%) MCAs in the symptomatic group (
P
=0.02), and 3/29 (10%) MCAs in the asymptomatic group (
P
=0.54). Nine of 11 (82%) symptomatic eyes with MES had ipsilateral ICA stenosis of ≥50%, as compared with 0/3 (0%) eyes in the asymptomatic group with MES (
P
=0.03). Both MES and ICA stenosis of >50% were present in 9/37 (24%) cases in the symptomatic and in 0/29 (0%) cases of the asymptomatic group (
P
=0.0036).

Conclusions—

The frequency and potential source of cerebral microemboli in symptomatic and asymptomatic retinal embolism are different. Cerebral microemboli are more frequent in symptomatic patients and are associated with ICA stenosis.
Processing Objects at Different Levels of Specificity
Authors: Tyler L. K. , Stamatakis E. A. , Bright P. , Acres K. , Abdallah S. , Rodd J. M. , Moss H. E.
Published: March 2004

How objects are represented and processed in the brain is a central topic in cognitive neuroscience. Previous studies have shown that knowledge of objects is represented in a featurebased distributed neural system primarily involving occipital and temporal cortical regions. Research with nonhuman primates suggest that these features are structured in a hierarchical system with posterior neurons in the inferior temporal cortex representing simple features and anterior neurons in the perirhinal cortex representing complex conjunctions of features (Bussey & Saksida, 2002; Murray & Bussey, 1999). On this account, the perirhinal cortex plays a crucial role in object identification by integrating information from different sensory systems into more complex polymodal feature conjunctions. We tested the implications of these claims for human object processing in an event-related fMRI study in which we presented colored pictures of common objects for 19 subjects to name at two levels of specificity-basic and domain. We reasoned that domain-level naming requires access to a coarsergrained representation of objects, thus involving only posterior regions of the inferior temporal cortex. In contrast, basic-level naming requires finer-grained discrimination to differentiate between similar objects, and thus should involve anterior temporal regions, including the perirhinal cortex. We found that object processing always activated the fusiform gyrus bilaterally, irrespective of the task, whereas the perirhinal cortex was only activated when the task required finer-grained discriminations. These results suggest that the same kind of hierarchical structure, which has been proposed for object processing in the monkey temporal cortex, functions in the human.
All Talk and No Action: A Transcranial Magnetic Stimulation Study of Motor Cortex Activation during Action Word Production
Authors: Oliveri Massimiliano , Finocchiaro Chiara , Shapiro Kevin , Gangitano Massimo , Caramazza Alfonso , Pascual-Leone Alvaro
Published: March 2004

A number of researchers have proposed that the premotor and motor areas are critical for the representation of words that refer to actions, but not objects. Recent evidence against this hypothesis indicates that the left premotor cortex is more sensitive to grammatical differences than to conceptual differences between words. However, it may still be the case that other anterior motor regions are engaged in processing a word's sensorimotor features. In the present study, we used singleand paired-pulse transcranial magnetic stimulation to test the hypothesis that left primary motor cortex is activated during the retrieval of words (nouns and verbs) associated with specific actions. We found that activation in the motor cortex increased for action words compared with non-action words, but was not sensitive to the grammatical category of the word being produced. These results complement previous findings and support the notion that producing a word activates some brain regions relevant to the sensorimotor properties associated with that word regardless of its grammatical category.
An Event-related fMRI Study of Artificial Grammar Learning in a Balanced Chunk Strength Design
Authors: Lieberman Matthew D. , Chang Grace Y. , Chiao Joan , Bookheimer Susan Y. , Knowlton Barbara J.
Published: March 2004

Artificial grammar learning (Reber, 1967) is a form of implicit learning in which cognitive, rather than motor, implicit learning has been found. After viewing a series of letter strings formed according to a finite state rule system, people are able to classify new letter strings as to whether or not they are formed according to these grammatical rules despite little conscious insight into the rule structure. Previous research has shown that these classification judgments are based on knowledge of abstract rules as well as superficial similarity (“chunk strength”) to training strings. Here we used event-related fMRI to identify neural regions involved in using both sources of information as test stimuli were designed to unconfound chunk strength from rule use. Using functional connectivity analyses, the extent to which the sources of information are complementary or competitive was also assessed. Activation in the right caudate was associated with rule adherence, whereas medial temporal lobe activations were associated with chunk strength. Additionally, functional connectivity analyses revealed caudate and medial temporal lobe activations to be strongly negatively correlated (r = −88) with one another during the performance of this task.
Neuronal Synchronization and Selective Color Processing in the Human Brain
Authors: Müller Matthias M. , Keil Andreas
Published: March 2004

In the present study, subjects selectively attended to the color of checkerboards in a feature-based attention paradigm. Induced gamma band responses (GBRs), the induced alpha band, and the event-related potential (ERP) were analyzed to uncover neuronal dynamics during selective feature processing. Replicating previous ERP findings, the selection negativity (SN) with a latency of about 160 msec was extracted. Furthermore, and similarly to previous EEG studies, a gamma band peak in a time window between 290 and 380 msec was found. This peak had its major energy in the 55to 70-Hz range and was significantly larger for the attended color. Contrary to previous human induced gamma band studies, a much earlier 40to 50-Hz peak in a time window between 160 and 220 msec after stimulus onset and, thus, concurrently to the SN was prominent with significantly more energy for attended as opposed to unattended color. The induced alpha band (9.8–11.7 Hz), on the other hand, exhibited a marked suppression for attended color in a time window between 450 and 600 msec after stimulus onset. A comparison of the time course of the 40to 50-Hz and 55to 70-Hz induced GBR, the induced alpha band, and the ERP revealed temporal coincidences for changes in the morphology of these brain responses. Despite these similarities in the time domain, the cortical source configuration was found to discriminate between induced GBRs and the SN. Our results suggest that large-scale synchronous high-frequency brain activity as measured in the human GBR play a specific role in attentive processing of stimulus features.