bluuebunny/crossref_metadata_2025 huggingface dataset:
Cooperative interactions among intestinal GATA factors in activating the rat liver fatty acid binding protein gene
Authors: Divine Joyce K. , Staloch Lora J. , Haveri Hanna , Rowley Christopher W. , Heikinheimo Markku , Simon Theodore C.
Published: April 2006

GATA-4, GATA-5, and GATA-6 are endodermal zinc-finger transcription factors that activate numerous enterocytic genes. GATA-4 and GATA-6 but not GATA-5 are present in adult murine small intestinal enterocytes, and we now report the simultaneous presence of all three GATA factors in murine small intestinal enterocytes before weaning age. An immunohistochemical survey detected enterocytic GATA-4 and GATA-6 at birth and 1 wk of age and GATA-5 at 1 wk but not birth. Interactions among GATA factors were explored utilizing a transgene constructed from the proximal promoter of the rat liver fatty acid binding protein gene ( Fabp1). GATA-4 and GATA-5 but not GATA-6 activate the Fabp1 transgene through a cognate binding site at −128. A dose-response assay revealed a maximum in transgene activation by both factors, where additional factor did not further increase transgene activity. However, at saturated levels of GATA-4, additional transgene activation was achieved by adding GATA-5 expression construct, and vice versa. Similar cooperativity occurred with GATA-5 and GATA-6. Identical interactions were observed with a target transgene consisting of a single GATA site upstream of a minimal promoter. Furthermore, GATA-4 and GATA-5 or GATA-5 and GATA-6 bound to each other in solution. These results are consistent with tethering of one GATA factor to the Fabp1 promoter through interaction with a second GATA factor to produce increased target gene activation. Cooperative target gene activation was specific to an intestinal cell line and may represent a mechanism by which genes are activated in the small intestinal epithelium during the period before weaning.
Crambene induces pancreatic acinar cell apoptosis via the activation of mitochondrial pathway
Authors: Cao Yang , Adhikari Sharmila , Ang Abel Damien , Clément Marie Véronique , Wallig Matthew , Bhatia Madhav
Published: April 2006

We investigated the apoptotic pathway activated by crambene (1-cyano-2-hydroxy-3-butene), a plant nitrile, on pancreatic acinar cells. As evidenced by annexin V-FITC staining, crambene treatment for 3 h induced the apoptosis but not necrosis of pancreatic acini. Caspase-3, -8, and -9 activities in acini treated with crambene were significantly higher than in untreated acini. Treatment with caspase-3, -8, and -9 inhibitors inhibited annexin V staining, as well as caspase-3 activity, pointing to an important role of these caspases in crambene-induced acinar cell apoptosis. The mitochondrial membrane potential was collapsed, and cytochrome c was released from the mitochondria in crambene-treated acini. Neither TNF-α nor Fas ligand levels were changed in pancreatic acinar cells after crambene treatment. These results provide evidence for the induction of pancreatic acinar cell apoptosis in vitro by crambene and suggest the involvement of mitochondrial pathway in pancreatic acinar cell apoptosis.
Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats
Authors: Huang Bing S. , Cheung Warren J. , Wang Hao , Tan Junhui , White Roselyn A. , Leenen Frans H. H.
Published: April 2006

Functional studies indicate that the sympathoexcitatory and pressor responses to an increase in cerebrospinal fluid (CSF) [Na+] by central infusion of Na+-rich artificial cerebrospinal fluid (aCSF) in Wistar rats are mediated in the brain by mineralocorticoid receptor (MR) activation, ouabain-like compounds (OLC), and AT1-receptor stimulation. In the present study, we examined whether increasing CSF [Na+] by intracerebroventricular infusion of Na+-rich aCSF activates MR and thereby increases OLC and components of the renin-angiotensin system in the brain. Male Wistar rats received via osmotic minipump an intracerebroventricular infusion of aCSF or Na+-rich aCSF, in some groups combined with intracerebroventricular infusion of spironolactone (100 ng/h), antibody Fab fragments (to bind OLC), or as control γ-globulins. After 2 wk of infusion, resting blood pressure and heart rate were recorded, OLC and aldosterone content in the hypothalamus were assessed by a specific ELISA or radioimmunoassay, and angiotensin-converting enzyme (ACE) and AT1-receptor binding densities in various brain nuclei were measured by autoradiography using 125I-labeled 351 A and 125I-labeled ANG II. When compared with intracerebroventricular aCSF, intracerebroventricular Na+-rich aCSF increased CSF [Na+] by ∼5 mmol/l, mean arterial pressure by ∼20 mmHg, heart rate by ∼65 beats/min, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Intracerebroventricular spironolactone did not affect CSF [Na+] but blocked the Na+-rich aCSF-induced increases in blood pressure and heart rate and OLC content. Intracerebroventricular Na+-rich aCSF increased ACE and AT1-receptor-binding densities in several brain nuclei, and Fab fragments blocked these increases. These data indicate that in Wistar rats, a chronic increase in CSF [Na+] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in AT1-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension.
CRP promotes monocyte-endothelial cell adhesion via Fcγ receptors in human aortic endothelial cells under static and shear flow conditions
Authors: Devaraj Sridevi , Davis Benjamin , Simon Scott I. , Jialal Ishwarlal
Published: April 2006

Monocyte-endothelial cell adhesion is a key early event in atherogenesis. C-reactive protein (CRP), a cardiovascular risk marker, is known to stimulate ICAM and VCAM in human aortic endothelial cells (HAEC) and induces monocyte-endothelial cell adhesion. In this study, we examined the mechanisms by which native CRP promotes monocyte-endothelial cell adhesion under static conditions and tested the effect of CRP on adhesion under shear flow. Incubation of HAEC with CRP (>25 μg/ml) upregulated NF-κB activity, and this resulted in a significant increase in ICAM (54% increase, P < 0.001), VCAM (41% increase, P < 0.01), and monocyte-endothelial cell adhesion (44% increase, P < 0.02) compared with those of control. Preincubation with antibodies to CD32 and CD64 but not CD16 effectively inhibited this activation. Blocking NF-κB activity with inhibitors or a dominant negative inhibitory κB significantly decreased ICAM, VCAM upregulation, and subsequent monocyte-endothelial cell adhesion. Preincubation with antibodies to CD32 and CD64 or transient transfection with small interference RNA to CD32 attenuated CRP-induced NF-κB activity, ICAM, VCAM, and monocyte-endothelial cell adhesion under static conditions. Also, the Syk kinase inhibitor piceatannol and MG-132, a proteasome degradation inhibitor, produced similar attenuation in NF-κB activity, ICAM, VCAM, and adhesion. Furthermore, CRP-activated endothelial cells supported monocyte rolling, arrest, and transmigration in shear flow (2 dyn/cm2), and this was also inhibited by preincubation with antibodies to CD32 and CD64. Thus, in HAEC, CRP upregulates monocyte-endothelial adhesion by activation of NF-κB through engaging the Fcγ receptors CD32 and CD64.
Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure
Authors: Münch Götz , Rosport Kai , Baumgartner Christine , Li Zhongmin , Wagner Silvia , Bültmann Andreas , Ungerer Martin
Published: April 2006

The sodium-calcium exchanger (NCX) is discussed as one of the key proteins involved in heart failure. However, the causal role and the extent to which NCX contributes to contractile dysfunction during heart failure are poorly understood. NCX overexpression was induced by infection with an adenovirus coding for NCX, which coexpressed green fluorescence protein (GFP) (AdNCX) by ex vivo gene transfer to nonfailing and failing rabbit cardiomyocytes. Myocardial gene transfer in rabbits in vivo was achieved by adenoviral delivery via aortic cross-clamping. Peak cell shortening of cardiomyocytes was determined photo-optically. Hemodynamic parameters in vivo were determined by echocardiography (fractional shortening) and tip catheter [maximal first derivative of left ventricular (LV) pressure (dP/d tmax); maximal negative derivative of LV pressure (−dP/d tmax)]. Peak cell shortening was depressed after NCX gene delivery in isolated nonfailing and in failing cardiomyocytes. In nonfailing rabbits in vivo, basal systolic contractility (fractional shortening and dP/d tmax) and maximum rate of LV relaxation (−dP/d tmax) in vivo were largely unaffected after NCX overexpression. However, during heart failure, long-term NCX overexpression over 2 wk significantly improved fractional shortening and dP/d tmax compared with AdGFP-infected rabbits, both without inotropic stimulation and after β-adrenergic stimulation with isoproterenol. −dP/d tmax was also improved after NCX overexpression in the failing rabbits group. These results indicate that short-term effects of NCX overexpression impair contractility of isolated failing and nonfailing rabbit cardiomyocytes. NCX overexpression over 2 wk in vivo does not seem to affect myocardial contractility in nonfailing rabbits. Interestingly, in vivo overexpression of NCX decreased the progression of systolic and diastolic contractile dysfunction and improved β-adrenoceptor-mediated contractile reserve in heart failure in rabbits in vivo.
Protective effects ofS-nitrosoalbumin on lung injury induced by hypoxia-reoxygenation in mouse model of sickle cell disease
Authors: de Franceschi Lucia , Malpeli Giorgio , Scarpa Aldo , Janin Anne , Muchitsch Eva Maria , Roncada Paola , Leboeuf Christhope , Corrocher Roberto , Beuzard Yves , Brugnara Carlo
Published: April 2006

Nitric oxide (NO) is a potential new therapeutic agent for sickle cell disease (SCD). We investigated the effects of NO donor on hypoxia-induced acute lung injury that occurs when transgenic sickle cell SAD mice are exposed to chronic hypoxia, a model for lung vasoocclusive sickle cell events. In wild-type and SAD mice, intraperitoneal injection of S-nitrosoalbumin (NO-Alb) produced no significant hematologic changes under room air conditions, whereas it induced mild temporary hypotension and inhibition of platelet aggregation. NO-Alb administration (300 mg/kg ip twice a day, equivalent to 7.5 μM NO) in wild-type and SAD mice exposed to 46 h of hypoxia (8% oxygen) followed by 2 h of normoxia resulted in 1) reduction of the hypoxia-induced increase in blood neutrophil count, 2) prevention of hypoxia-induced increased IL-6 and IL-1β levels in bronchoalveolar lavage, 3) reduction of the lung injury induced by hypoxia-reoxygenation, 4) prevention of thrombus formation, and 5) prevention of hypoxia-induced increase of lung matrix metalloproteinase-9 gene expression. These effects provide new insights into the possible use of NO-Alb in the treatment of acute lung injury in SCD.
Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells
Authors: Copland Ian B. , Reynaud Denis , Pace-Asciak Cecil , Post Martin
Published: April 2006

Mechanical ventilation is the primary supportive treatment for infants and adults suffering from severe respiratory failure. Adverse mechanical ventilation (overdistension of the lung) triggers a proinflammatory response. Along with cytokines, inflammatory mediators such as bioactive lipids are involved in the regulation of the inflammatory response. The arachidonic acid pathway is a key source of bioactive lipid mediators, including prostanoids. Although ventilation has been shown to influence the production of prostanoids in the lung, the mechanotransduction pathways are unknown. Herein, we established that cyclic stretch of fetal lung epithelial cells, but not fibroblasts, can evoke an extremely sensitive, rapid alteration in eicosanoid metabolism through a cyclooxygenase (COX)-2 dependent mechanism. Cyclic stretch significantly increased PGI2, PGF2α, PGD2, PGE2, and thromboxane B2levels in the media of epithelial cells, but did not alter leukotriene B4or 12-hydroxyeicosatetraenoic acid levels. Inhibition of COX-2, but not COX-1, attenuated the cyclic stretch-induced PG increase in the media, suggesting that cyclic stretch primarily affected PG synthesis. Substrate (free arachidonic acid) availability for PG generation was increased because of a cyclic stretch-induced activation of cytosolic phospholipase A2(cPLA2) via an influx of extracellular calcium and phosphorylation by mitogen-activated protein kinase, p44/42MAPK. The data are compatible with cPLA2and COX-2 being intimately involved in regulating the injury response to adverse mechanical ventilation.
Folate Supplementation During Pregnancy Improves Offspring Cardiovascular Dysfunction Induced by Protein Restriction
Authors: Torrens Christopher , Brawley Lee , Anthony Frederick W. , Dance Caroline S. , Dunn Rebecca , Jackson Alan A. , Poston Lucilla , Hanson Mark A.
Published: April 2006

Dietary protein restriction in the rat compromises the maternal cardiovascular adaptations to pregnancy and leads to raised blood pressure and endothelial dysfunction in the offspring. In this study we have hypothesized that dietary folate supplementation of the low-protein diet will improve maternal vascular function and also restore offspring cardiovascular function. Pregnant Wistar rats were fed either a control (18% casein) or protein-restricted (9% casein) diet ±5 mg/kg folate supplement. Function of isolated maternal uterine artery and small mesenteric arteries from adult male offspring was assessed, systolic blood pressure recorded, and offspring thoracic aorta levels of endothelial nitric oxide (NO) synthase mRNA measured. In the uterine artery of late pregnancy dams, vasodilatation to vascular endothelial growth factor was attenuated in the protein-restricted group but restored with folate supplementation, as was isoprenaline-induced vasodilatation (
P
<0.05). In male offspring, protein restriction during pregnancy led to raised systolic blood pressure (
P
<0.01), impaired acetylcholine-induced vasodilatation (
P
<0.01), and reduced levels of endothelial NO synthase mRNA (
P
<0.05). Maternal folate supplementation during pregnancy prevented this elevated systolic blood pressure associated with a protein restriction diet. With folate supplementation, endothelium-dependent vasodilatation and endothelial NO synthase mRNA levels were not significantly different from either the control or protein-restricted groups. Maternal folate supplementation of the control diet had no effect on blood pressure or vasodilatation. This study supports the hypothesis that folate status in pregnancy can influence fetal development and, thus, the risks of cardiovascular disease in the next generation. The concept of developmental origins of adult disease focuses predominately on fetal life but must also include a role for maternal cardiovascular function.
Office and Ambulatory Blood Pressure Are Independently Associated With Albuminuria in Older Subjects With Type 2 Diabetes
Authors: Moran Andrew , Palmas Walter , Pickering Thomas G. , Schwartz Joseph E. , Field Lesley , Weinstock Ruth S. , Shea Steven
Published: April 2006

Blood pressure strongly predicts microalbuminuria and later progression to renal failure in people with diabetes. Ambulatory blood pressure monitoring seems to be superior to office blood pressure in predicting progression to microalbuminuria in type 1 diabetes. The associations of ambulatory blood pressure with office blood pressure and microalbuminuria in type 2 diabetes remain unclear. We studied the association of office blood pressure taken with an automated device and ambulatory blood pressure with spot urine albumin:creatinine ratio in 1180 older people with type 2 diabetes participating in the Informatics for Diabetes Education and Telemedicine Study. Office and awake systolic blood pressure were independently associated with albuminuria (
P
<0.001 for both) in a multivariate linear regression analysis that adjusted for age, gender, duration of diabetes, hemoglobin A1c, number of antihypertensive medications, and use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Twelve percent of participants had well-controlled office blood pressure but not ambulatory blood pressure, whereas 14% had well-controlled ambulatory but not office blood pressure. The prevalence of microalbuminuria and macroalbuminuria in these subgroups was intermediate between those with well-controlled or uncontrolled blood pressure by both methods. We found, in a multiethnic group of older subjects with type 2 diabetes, that office systolic blood pressure and awake systolic ambulatory blood pressure exhibited independent associations with degree of albuminuria.
Electrocardiographic QRS Duration and the Risk of Congestive Heart Failure
Authors: Dhingra Ravi , Pencina Michael J. , Wang Thomas J. , Nam Byung-Ho , Benjamin Emelia J. , Levy Daniel , Larson Martin G. , Kannel William B. , D’Agostino Ralph B. , Vasan Ramachandran S.
Published: April 2006

Prolonged electrocardiographic QRS duration is frequently observed in congestive heart failure (CHF) patients. We hypothesized that CHF risk increases with longer QRS interval in individuals free of CHF. We evaluated 1759 Framingham Study participants (mean age, 69 years; 63% women) without prior myocardial infarction or CHF who attended a routine examination. QRS duration was analyzed as a continuous (log-transformed) and a categorical variable [referent, <100 ms; incomplete bundle branch block (BBB), 100 to 119 ms; complete BBB, ≥120 ms]. During follow-up (mean, 12.7 years), 324 participants (205 women) developed CHF. CHF incidence increased across the 3 baseline QRS duration categories in both sexes. Each SD increment in log-QRS duration was associated with a multivariable-adjusted 23% increase in CHF risk [95% confidence interval [CI] 8% to 38%;
P
<0.001]. In time- dependent models with QRS category and risk factors updated every 2 years, incomplete BBB was associated with a 1.4-fold (95% CI, 1.05 to 1.96;
P
=0.03) and complete BBB with a 1.7-fold (95% CI, 1.28 to 2.35;
P
<0.001) risk of CHF. These associations were maintained on adjustment for baseline left ventricular mass. In our community-based sample, longer electrocardiographic QRS was associated with increased CHF risk, consistent with the hypothesis that depolarization delay may increase CHF risk.
Rho Kinase Polymorphism Influences Blood Pressure and Systemic Vascular Resistance in Human Twins
Authors: Seasholtz Tammy M. , Wessel Jennifer , Rao Fangwen , Rana Brinda K. , Khandrika Srikrishna , Kennedy Brian P. , Lillie Elizabeth O. , Ziegler Michael G. , Smith Douglas W. , Schork Nicholas J. , Heller Brown Joan , O’Connor Daniel T.
Published: April 2006

The Rho/Rho kinase (ROCK) pathway is implicated in experimental hypertension. We, therefore, explored the role of ROCK2 genetic variation in human blood pressure (BP) regulation, exploiting the advantages of a human twin sample to probe heritability. The focus of this work is the common nonsynonymous variant at ROCK2: Thr431Asn. Cardiovascular and autonomic traits displayed substantial heritability (from ≈33% to 71%;
P
<0.05). The Asn/Asn genotype (compared with Asn/Thr or Thr/Thr) was associated with greater resting systolic (
P
<0.001), diastolic (
P
<0.0001), and mean BP (
P
<0.0001); allelic variation at ROCK2 accounted for up to ≈5% of BP variation (
P
<0.0001). Systemic vascular resistance was higher in Asn/Asn individuals (
P
=0.049), whereas cardiac output, large artery compliance, and vasoactive hormone secretion were not different. Coupling of the renin-angiotensin system to systemic resistance and BP was diminished in Asn/Asn homozygotes, suggesting genetic pleiotropy of Thr431Asn, confirmed by bivariate genetic analyses. The Asn/Asn genotype also predicted higher BP after environmental (cold) stress. The rise in heart rate after cold was less pronounced in Asn/Asn individuals, consistent with intact baroreceptor function, and baroreceptor slope was not influenced by genotype. Common genetic variation (Thr431Asn) at ROCK2 predicts increased BP, systemic vascular resistance (although not large artery compliance), and resistance in response to the endogenous renin-angiotensin system, indicating a resistance vessel-based effect on elevated BP. The results suggest that common variation in ROCK2 exerts systemic resistance-mediated changes in BP, documenting a novel mechanism for human circulatory control, and suggesting new possibilities for diagnostic profiling and treatment of subjects at risk of developing hypertension.
Kir3-Based Inward Rectifier Potassium Current
Authors: Cha Tae-Joon , Ehrlich Joachim R. , Chartier Denis , Qi Xiao-Yan , Xiao Ling , Nattel Stanley
Published: April 2006

Background—We previously characterized a novel K+current (IKH) with properties of constitutively active acetylcholine-related current in dog atrium.IKHis sensitive to tertiapin-Q (IC50≈10 nmol/L), a highly selective Kir3 current blocker. This study assessed the role ofIKHin atrial tachycardia (AT)–remodeled canine left atrium (LA) with the use of tertiapin-Q as a probe.

Methods and Results—Dogs were subjected to 7 to 13 days of AT (400 bpm). Coronary-perfused LA preparations were studied intact or subjected to cardiomyocyte isolation.IKHwas recorded with patch-clamp methods. AT pacing increased time-dependent hyperpolarization-activated current (IKH) at −110 mV from −1.8±0.3 (control) to −3.4±0.5 pA/pF (AT) and the 100-nmol/L tertiapin-sensitive component from −1.5±0.4 (control) to −3.3±0.6 pA/pF (AT). Prolonged atrial tachyarrhythmias could be induced with single extrastimuli in AT-remodeled, but not control, preparations, reflecting the atrial fibrillation–promoting effects of AT remodeling. In AT-remodeled preparations, tachyarrhythmia duration averaged 11.0±5.2 seconds, with a cycle length of 108±6 ms. Tertiapin-Q decreased tachyarrhythmia duration (to 0.6±0.1 second;P<0.001) and increased tachyarrhythmia cycle length (to 175±10 ms;P<0.001). Atrial action potential duration (APD) was increased 65±6% by tertiapin in AT-remodeled hearts versus 19±2% (P<0.001) in control. In 2 AT-remodeled preparations, tachyarrhythmia lasted uninterrupted for >20 minutes; tertiapin-Q slowed and then terminated arrhythmia in both. Tertiapin had no effect on left ventricular cardiomyocyte currents or APD.

Conclusions—AT remodeling increasesIKH, and a highly selective Kir3 current antagonist, tertiapin-Q, increases APD and suppresses atrial tachyarrhythmias in AT-remodeled preparations without affecting ventricular electrophysiology. Constitutive acetylcholine-related K+current contributes to AT-remodeling effects in dogs and is a potentially interesting antiarrhythmic target.
Overexpression of Mitochondrial Peroxiredoxin-3 Prevents Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice
Authors: Matsushima Shouji , Ide Tomomi , Yamato Mayumi , Matsusaka Hidenori , Hattori Fumiyuki , Ikeuchi Masaki , Kubota Toru , Sunagawa Kenji , Hasegawa Yasuhiro , Kurihara Tatsuya , Oikawa Shinzo , Kinugawa Shintaro , Tsutsui Hiroyuki
Published: April 2006

Background—

Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process.

Methods and Results—

We created MI in 12- to 16-week-old, male Prx-3–transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid–reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean±SEM, 1.5±0.2 vs 2.2±0.2 nmol/mg protein; n=8 each,
P
<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56±1% vs 55±1%; n=6 each,
P
=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice.

Conclusions—

Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.
Effects of Gap Geometry on Conduction Through Discontinuous Radiofrequency Lesions
Authors: Pérez Francisco J. , Wood Mark A. , Schubert Christine M.
Published: April 2006

Background—

Gaps of sufficient cross-sectional dimensions within linear radiofrequency (RF) lesions may allow conduction through the lesion. The purpose of this study was to examine the effects of different gap geometries on conduction through discontinuous RF lesions.

Methods and Results—

Radiofrequency lesions were created in isolated, perfused rabbit right ventricular (RV) free wall preparations to produce gaps with 3 different lesion geometries: straight, bifurcated, and angled (n=10 each group). Angled preparations contained 2 right angles within the conduction path. Optical mapping was used to assess bidirectional conduction through the myocardium before and after gap formation during pacing at 1000-, 400-, and 200-ms cycle lengths. Histological analysis was performed on each preparation after optical mapping. After lesion formation, 9 of 10 straight gap preparations and 1 of 10 angled gap preparations demonstrated bidirectional conduction (
P
<0.001) at all cycle lengths. Nine of 10 bifurcated gap preparations demonstrated bidirectional conduction and 1 demonstrated unidirectional conduction at all cycle lengths. Two bifurcated gap preparations showed rate-dependent unidirectional 2:1 conduction. All unidirectional and rate-dependent block occurred during impulse propagation in the direction of diverging arms of the bifurcation. The occurrence of bidirectional conduction in the gaps was associated with the gap geometry (
P
<0.0001). Histological analysis confirmed the continuity of viable myocardium transmurally throughout the length of the gap in each preparation. The sites of conduction block were demonstrated to be just after the first angle in the conduction path for angled gaps and at the branch point of a bifurcated gap. The predominant myofiber orientation was changed relative to the conduction path at angulations of the gaps. Flecainide (0.1 μmol/L) produced bidirectional conduction block in straight and bifurcated gap preparations with bidirectional conduction at baseline.

Conclusions—

Conduction through discontinuities in RF lesions is associated with gap geometry. Complex gap geometry may allow for unidirectional and/or rate-dependent block. Gaps within RF lesions are susceptible to pharmacological blockade.
Evidence of a Dominant Backward-Propagating “Suction” Wave Responsible for Diastolic Coronary Filling in Humans, Attenuated in Left Ventricular Hypertrophy
Authors: Davies Justin E. , Whinnett Zachary I. , Francis Darrel P. , Manisty Charlotte H. , Aguado-Sierra Jazmin , Willson Keith , Foale Rodney A. , Malik Iqbal S. , Hughes Alun D. , Parker Kim H. , Mayet Jamil
Published: April 2006

Background—

Coronary blood flow peaks in diastole when aortic blood pressure has fallen. Current models fail to completely explain this phenomenon. We present a new approach—using wave intensity analysis—to explain this phenomenon in normal subjects and to evaluate the effects of left ventricular hypertrophy (LVH).

Method and Results—

We measured simultaneous pressure and Doppler velocity with intracoronary wires in the left main stem, left anterior descending, and circumflex arteries of 20 subjects after a normal coronary arteriogram. Wave intensity analysis was used to identify and quantify individual pressure and velocity waves within the coronary artery circulation. A consistent pattern of 6 predominating waves was identified. Ninety-four percent of wave energy, accelerating blood forward along the coronary artery, came from 2 waves: first a pushing wave caused by left ventricular ejection—the dominant forward-traveling pushing wave; and later a suction wave caused by relief of myocardial microcirculatory compression—the dominant backward-traveling suction wave. The dominant backward-traveling suction wave (18.2±13.7×10
3
W m
−2
s
−1
, 30%) was larger than the dominant forward-traveling pushing wave (14.3±17.6×10
3
W m
−2
s
−1
, 22.3%,
P
=0.001) and was associated with a substantially larger increment in coronary blood flow velocity (0.51 versus 0.14 m/s,
P
<0.001). In LVH, the dominant backward-traveling suction wave percentage was significantly decreased (33.1% versus 26.9%,
P
=0.01) and inversely correlated with left ventricular septal wall thickness (
r
=−0.52,
P
<0.02).

Conclusions—

Six waves predominantly drive human coronary blood flow. Coronary flow peaks in diastole because of the dominance of a “suction” wave generated by myocardial microcirculatory decompression. This is significantly reduced in LVH.
Progression of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in Relation to Incident Type 2 Diabetes
Authors: Festa Andreas , Williams Ken , Tracy Russell P. , Wagenknecht Lynne E. , Haffner Steven M.
Published: April 2006

Background—

Several studies have shown that fibrinolytic and coagulation abnormalities as well as low-grade inflammation predict cardiovascular disease and type 2 diabetes. We studied in the Insulin Resistance Atherosclerosis Study the relation of incident diabetes to dynamic changes of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen.

Methods and Results—

After a follow-up of 5.2 years, diabetes developed in 140 (16.6%) of 843 individuals (57% women; mean age [range], 54.7 [40, 69] years) (converters versus nonconverters). Baseline and follow-up levels of PAI-1 and fibrinogen (demographically and smoking adjusted) were higher in converters versus nonconverters (mean [SE]): at baseline, 23.7 ng/mL (1.5) versus 14.5 (0.4) and 286.2 mg/dL (4.8) versus 273.6 (2.1); at follow-up, 45.3 ng/mL (3.2) versus 25.9 (0.8) and 292.0 mg/dL (5.6) versus 275.2 (2.5); all
P
<0.05. In a demographically and smoking-adjusted logistic regression model, the change in PAI-1 was related to incident diabetes (OR for a 1-SD change [CI], 1.75 [1.37, 2.22];
P
<0.001) after adjusting for baseline PAI-1 levels. After further adjusting for insulin sensitivity (S
I
) or waist, change in PAI-1 remained significantly related to incident diabetes (OR, 1.66 [1.28, 2.15], and 1.64 [1.28, 2.10];
P
<0.001). In contrast, change in fibrinogen was not significantly related to incident diabetes.

Conclusions—

Progression of PAI-1 levels over time, in addition to high baseline PAI-1 levels, is associated with incident diabetes. PAI-1 levels (but not fibrinogen) further increase with the rising glucose levels and the development of diabetes. These findings extend the current knowledge on the relation of fibrinolysis and coagulation abnormalities to the development of type 2 diabetes.
How Environmental is African Traditional Religion?
Authors: Taringa Nisbert
Published: April 2006

This article examines some of the beliefs and practices underlying traditional African religion's attitudes to nature with reference to Shona religion of Zimbabwe. At the theoretical level, assuming a romantic view of Shona attitudes to nature, it is possible to conclude that Shona traditional religion is necessarily environmentally friendly. The strong beliefs in ancestral spirits (midzimu), pan-vitalism, kinship, taboo and totems have the potential to bear testimony to this. The aim of this article is to critically examine the extent of the claims that Shona traditional religion is environmentally friendly. It shows that Shona attitudes to nature are in fact discriminative and ambivalent. I argue that the ecological attitude of traditional African religion is more based on fear or respect of ancestral spirits than on respect for nature itself. As a result we need to re-examine Shona attitudes to nature if Shona traditional religion is to re-emerge as a stronger environmental force in the global village. After introductory remarks the article gives an overview background about the Shona focusing on their socio-political organization, world-view and religion. An examination of Shona attitudes to nature focusing on the land, animals, and plant life and water bodies follows. After this there is a reflection on the ethical consequences of Shona attitudes to nature. The last part considers the limits of the romantic view of Shona attitudes to nature.
GFDL's CM2 Global Coupled Climate Models. Part II: The Baseline Ocean Simulation
Authors: Gnanadesikan Anand , Dixon Keith W. , Griffies Stephen M. , Balaji V. , Barreiro Marcelo , Beesley J. Anthony , Cooke William F. , Delworth Thomas L. , Gerdes Rudiger , Harrison Matthew J. , Held Isaac M. , Hurlin William J. , Lee Hyun-Chul , Liang Zhi , Nong Giang , Pacanowski Ronald C. , Rosati Anthony , Russell Joellen , Samuels Bonita L. , Song Qian , Spelman Michael J. , Stouffer Ronald J. , Sweeney Colm O. , Vecchi Gabriel , Winton Michael , Wittenberg Andrew T. , Zeng Fanrong , Zhang Rong , Dunne John P.
Published: April 2006

The current generation of coupled climate models run at the Geophysical Fluid Dynamics Laboratory (GFDL) as part of the Climate Change Science Program contains ocean components that differ in almost every respect from those contained in previous generations of GFDL climate models. This paper summarizes the new physical features of the models and examines the simulations that they produce. Of the two new coupled climate model versions 2.1 (CM2.1) and 2.0 (CM2.0), the CM2.1 model represents a major improvement over CM2.0 in most of the major oceanic features examined, with strikingly lower drifts in hydrographic fields such as temperature and salinity, more realistic ventilation of the deep ocean, and currents that are closer to their observed values. Regional analysis of the differences between the models highlights the importance of wind stress in determining the circulation, particularly in the Southern Ocean. At present, major errors in both models are associated with Northern Hemisphere Mode Waters and outflows from overflows, particularly the Mediterranean Sea and Red Sea.
GFDL's CM2 Global Coupled Climate Models. Part III: Tropical Pacific Climate and ENSO
Authors: Wittenberg Andrew T. , Rosati Anthony , Lau Ngar-Cheung , Ploshay Jeffrey J.
Published: April 2006

Multicentury integrations from two global coupled ocean–atmosphere–land–ice models [Climate Model versions 2.0 (CM2.0) and 2.1 (CM2.1), developed at the Geophysical Fluid Dynamics Laboratory] are described in terms of their tropical Pacific climate and El Niño–Southern Oscillation (ENSO). The integrations are run without flux adjustments and provide generally realistic simulations of tropical Pacific climate. The observed annual-mean trade winds and precipitation, sea surface temperature, surface heat fluxes, surface currents, Equatorial Undercurrent, and subsurface thermal structure are well captured by the models. Some biases are evident, including a cold SST bias along the equator, a warm bias along the coast of South America, and a westward extension of the trade winds relative to observations. Along the equator, the models exhibit a robust, westward-propagating annual cycle of SST and zonal winds. During boreal spring, excessive rainfall south of the equator is linked to an unrealistic reversal of the simulated meridional winds in the east, and a stronger-than-observed semiannual signal is evident in the zonal winds and Equatorial Undercurrent.

Both CM2.0 and CM2.1 have a robust ENSO with multidecadal fluctuations in amplitude, an irregular period between 2 and 5 yr, and a distribution of SST anomalies that is skewed toward warm events as observed. The evolution of subsurface temperature and current anomalies is also quite realistic. However, the simulated SST anomalies are too strong, too weakly damped by surface heat fluxes, and not as clearly phase locked to the end of the calendar year as in observations. The simulated patterns of tropical Pacific SST, wind stress, and precipitation variability are displaced 20°–30° west of the observed patterns, as are the simulated ENSO teleconnections to wintertime 200-hPa heights over Canada and the northeastern Pacific Ocean. Despite this, the impacts of ENSO on summertime and wintertime precipitation outside the tropical Pacific appear to be well simulated. Impacts of the annual-mean biases on the simulated variability are discussed.
GFDL's CM2 Global Coupled Climate Models. Part IV: Idealized Climate Response
Authors: Stouffer R. J. , Broccoli A. J. , Delworth T. L. , Dixon K. W. , Gudgel R. , Held I. , Hemler R. , Knutson T. , Lee Hyun-Chul , Schwarzkopf M. D. , Soden B. , Spelman M. J. , Winton M. , Zeng Fanrong
Published: April 2006

The climate response to idealized changes in the atmospheric CO2 concentration by the new GFDL climate model (CM2) is documented. This new model is very different from earlier GFDL models in its parameterizations of subgrid-scale physical processes, numerical algorithms, and resolution. The model was constructed to be useful for both seasonal-to-interannual predictions and climate change research. Unlike previous versions of the global coupled GFDL climate models, CM2 does not use flux adjustments to maintain a stable control climate. Results from two model versions, Climate Model versions 2.0 (CM2.0) and 2.1 (CM2.1), are presented.

Two atmosphere–mixed layer ocean or slab models, Slab Model versions 2.0 (SM2.0) and 2.1 (SM2.1), are constructed corresponding to CM2.0 and CM2.1. Using the SM2 models to estimate the climate sensitivity, it is found that the equilibrium globally averaged surface air temperature increases 2.9 (SM2.0) and 3.4 K (SM2.1) for a doubling of the atmospheric CO2 concentration. When forced by a 1% per year CO2 increase, the surface air temperature difference around the time of CO2 doubling [transient climate response (TCR)] is about 1.6 K for both coupled model versions (CM2.0 and CM2.1). The simulated warming is near the median of the responses documented for the climate models used in the 2001 Intergovernmental Panel on Climate Change (IPCC) Working Group I Third Assessment Report (TAR).

The thermohaline circulation (THC) weakened in response to increasing atmospheric CO2. By the time of CO2 doubling, the weakening in CM2.1 is larger than that found in CM2.0: 7 and 4 Sv (1 Sv ≡ 106 m3 s−1), respectively. However, the THC in the control integration of CM2.1 is stronger than in CM2.0, so that the percentage change in the THC between the two versions is more similar. The average THC change for the models presented in the TAR is about 3 or 4 Sv; however, the range across the model results is very large, varying from a slight increase (+2 Sv) to a large decrease (−10 Sv).
Assessing Global Vegetation–Climate Feedbacks from Observations*
Authors: Liu Zhengyu , Notaro M. , Kutzbach J. , Liu Naizhuang
Published: April 2006

The feedback between global vegetation greenness and surface air temperature and precipitation is assessed using remote sensing observations of monthly fraction of photosynthetically active radiation (FPAR) for 1982 to 2000 with a 2.5° grid resolution. Lead/lag correlations are used to infer vegetation–climate interactions. Furthermore, a statistical method is used to quantify the efficiency of vegetation feedback on climate in the observations. This feedback analysis provides a first quantitative assessment of global vegetation feedback on climate. In northern mid- and high latitudes, vegetation variability is found to be driven predominantly by temperature; in the meantime, vegetation also exerts a strong positive feedback on temperature with the feedback accounting for over 10%–25% of the total monthly temperature variance. The strongest positive feedback occurs in the boreal regions of southern Canada/northern United States, northern Europe, and southern Siberia, where the feedback efficiency exceeds 1°C (0.1 FPAR)−1. Over most of the Tropics and subtropics (outside the equatorial rain belt), vegetation is driven primarily by precipitation. However, little vegetation feedback is found on local precipitation when averaged year-round, with the feedback explained variance usually accounting for less than 5% of the total precipitation variance. Nevertheless, in a few isolated small regions such as Northeast Brazil, East Africa, East Asia, and northern Australia, there appears to be some positive vegetation feedback on local precipitation, with the feedback efficiency over 1 cm month−1 (0.1 FPAR)−1. Further studies suggest a significant seasonal variation of the vegetation feedback in some regions. A preliminary analysis also seems to suggest an enhanced intensity of the vegetation feedback, especially on precipitation, at longer time scales and over a larger grid box area. Limitations and implications of the assessment of vegetation feedback are also discussed. The assessed vegetation feedback is shown to be valuable for the evaluation of vegetation–climate feedback in coupled climate–vegetation models.
Attributes of Several Methods for Detecting Discontinuities in Mean Temperature Series
Authors: DeGaetano Arthur T.
Published: April 2006

Simulated annual temperature series are used to compare seven homogenization procedures. The two that employ likelihood ratio tests routinely outperform other methods in their ability to identify modest (0.33°C; 0.6 standard deviation anomaly) shifts in the mean. The percentage of imposed shifts that are detected by these methods is similar to that based on tests that rely on a priori metadata information concerning the position of potential shifts. These methods, along with a two-phase regression approach, are also best at identifying and placing multiple shifts within a single time series. Although the regression procedure is better able to detect multiple breaks that are separated by relatively short time intervals, in its published form it suffers from a higher-than-expected Type I error rate. This was also found to be a problem with a metadata-based procedure currently in operational use. The likelihood tests are strongly influenced by the presence of trends in the difference series and short (<20 yr) series length.

The ability of a given procedure to detect a discontinuity is predominately influenced by the magnitude of the discontinuity relative to the standard deviation of the data series being evaluated. Data series length, correlation between the test series and its associated reference series, and test series autocorrelation also influence test performance. These features were not considered in previous homogenization method comparisons.

Discontinuities with magnitudes less than 0.6 times the standard deviation of the time series represent the lower limit for homogenization. Based on the most effective homogenization techniques, 10% of the 1.25 standard deviation discontinuities are likely to remain in climatic data series, unless reference station correlations are exceptional or quality station metadata are available.
Measurement Requirements for Climate Monitoring of Upper-Air Temperature Derived from Reanalysis Data
Authors: Seidel Dian J. , Free Melissa
Published: April 2006

Using a reanalysis of the climate of the past half century as a model of temperature variations over the next half century, tests of various data collection protocols are made to develop recommendations for observing system requirements for monitoring upper-air temperature. The analysis focuses on accurately estimating monthly climatic data (specifically, monthly average temperature and its standard deviation) and multidecadal trends in monthly temperatures at specified locations, from the surface to 30 hPa. It does not address upper-air network size or station location issues.

The effects of reducing the precision of temperature data, incomplete sampling of the diurnal cycle, incomplete sampling of the days of the month, imperfect long-term stability of the observations, and changes in observation schedule are assessed. To ensure accurate monthly climate statistics, observations with at least 0.5-K precision, made at least twice daily, at least once every two or three days are sufficient. Using these same criteria, and maintaining long-term measurement stability to within 0.25 (0.1) K, for periods of 20 to 50 yr, errors in trend estimates can be avoided in at least 90% (95%) of cases. In practical terms, this requires no more than one intervention (e.g., instrument change) over the period of record, and its effect must be to change the measurement bias by no more than 0.25 (0.1) K. The effect of the first intervention dominates the effects of subsequent, uncorrelated interventions. Changes in observation schedule also affect trend estimates. Reducing the number of observations per day, or changing the timing of a single observation per day, has a greater potential to produce errors in trends than reducing the number of days per month on which observations are made.

These findings depend on the validity of using reanalysis data to approximate the statistical nature of future climate variations, and on the statistical tests employed. However, the results are based on conservative assumptions, so that adopting observing system requirements based on this analysis should result in a data archive that will meet climate monitoring needs over the next 50 yr.