bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Chronic Deep Brain Stimulation of the Subthalamic Nucleus for Frontal Lobe Epilepsy: Subtraction SPECT Analysis
Authors: Shon Young-Min , Lee Kyung Jin , Kim Hye Jin , Chung Yong-An , Ahn Kook Jin , Kim Yeong In , Yang Dong Won , Kim Bum Saeng
Published: July 2005

Objectives: Experimental data and case reports of patients with intractable epilepsy treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN) suggest a considerable anticonvulsant effect. However, no satisfactory mechanisms of action have yet been elucidated. We investigated the putative therapeutic mechanisms of DBS from cerebral perfusion changes as measured by subtracting the SPECT image of the pre-DBS period from that of the chronic post-DBS state. Methods: Two patients who had previous resective surgery on their right frontal cortices with or without anterior callosotomy were selected for DBS of the STN. Both of them showed frequent bilateral asymmetric tonic seizures (left > right) with rare drop attacks, and 1 patient’s seizure frequency was more than 15/month during the pre-DBS period. They had both taken more than four antiepileptic agents for more than 10 years. After video-EEG monitoring, the irritative zones of the brain were delineated. The regional cerebral blood flow (rCBF) changes between the two SPECT images (pre-DBS and post-DBS after at least 6 months) were analyzed by SPECT subtraction with the volumetric MRI coregistration method using Analyze 5.0 software. Results: After chronic STN DBS (18 months, case 1; 6 months, case 2), both patients experienced markedly reduced seizure frequencies (86.7% reduction in patient 1, 88.6% in patient 2). In patient 1, the increased rCBF was observed in the right frontal areas (dorsolateral and inferior frontal area), which corresponded to the irritative zones as confirmed by previous EEG recording. Unexpectedly, there was definite hyperperfusion in the right superior and inferior temporal areas as well as rCBF increase in the right superior frontal area (SMA) in patient 2. Conclusions: We demonstrated that the cerebral perfusion increase in the irritative zones of epilepsy patients is associated with favorable seizure reduction after STN DBS in 2 cases of frontal lobe epilepsy. Although the exact mechanism remains unknown, our findings suggest that the perfusion changes after STN DBS in frontal lobe epilepsy patients are quite different from those in subjects with Parkinson’s disease. Our preliminary data suggest the clinical relevance of subtraction SPECT imaging in assessing the postprocedural outcome as well as the characteristics of SPECT perfusion patterns in other epilepsy syndromes.
Angiotensin II–Mediated Phenotypic Cardiomyocyte Remodeling Leads to Age-Dependent Cardiac Dysfunction and Failure
Authors: Domenighetti Andrea A. , Wang Qing , Egger Marcel , Richards Stephen M. , Pedrazzini Thierry , Delbridge Lea M.D.
Published: July 2005

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II–mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (≈45% reduction in dP/dt
max
and dP/dt
min
at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca
2+
transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.
Differing Effects of Mineralocorticoid Receptor–Dependent and –Independent Potassium-Sparing Diuretics on Fibrinolytic Balance
Authors: Ma Ji , Albornoz Francisco , Yu Chang , Byrne Daniel W. , Vaughan Douglas E. , Brown Nancy J.
Published: July 2005

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen (
P
=0.006 for drug effect). In normotensive subjects, triamterene (from 10.1±7.8 to 16.9±9.9 ng/mL at 9
am
,
P
=0.019; from 7.6±5.4 to 11.5±7.3 ng/mL at 11
am
,
P
=0.027; from 9.3±7.7 to 13.7±8.5 ng/mL for average of all time points,
P
=0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0±23.4 to 16.7±19.0 ng/mL at 10
am
,
P
=0.041; from 17.5±21.7 to 12.7±16.8 ng/mL at 11
am
,
P
=0.043; from 20.3±22.6 to 16.6±19.7 ng/mL for average of all time points,
P
=0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene (
P
=0.014), hypertension (
P
=0.002), and PAI-1 response to HCTZ (
P
=0.019), with a trend for aldosterone (
P
=0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.
Comparison of Blood Pressure–Associated Risk of Intracerebral Hemorrhage and Subarachnoid Hemorrhage
Authors: Kim Hyeon Chang , Nam Chung Mo , Jee Sun Ha , Suh Il
Published: July 2005

Intracerebral hemorrhage and subarachnoid hemorrhage have different pathogeneses and risk factor profiles. However, little information is available on the difference between intracerebral and subarachnoid hemorrhages in relation to blood pressure. We prospectively investigated the relationships between blood pressure and risks of stroke subtypes. We measured blood pressure and other cardiovascular risk factors in 100 147 men and 59 558 women 35 to 59 years of age in 1990 and 1992. Outcomes were fatal and nonfatal events of stroke and its subtypes from 1993 to 2002. Independent relationships between baseline blood pressure and stroke subtypes were assessed using Cox’s proportional hazard models. During the 10 years, 1714 ischemic and 1159 hemorrhagic strokes (742 intracerebral and 308 subarachnoid hemorrhages) occurred. Blood pressure was related more closely with hemorrhagic stroke than ischemic stroke, and the difference was more prominent in women. Among the subtypes of hemorrhagic stroke, intracerebral hemorrhage was more closely related with blood pressure than subarachnoid hemorrhage. For each 20 mm Hg increase in systolic blood pressure, adjusted relative risks of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were 1.79 (95% confidence interval, 1.68 to 1.90), 2.48 (2.30 to 2.68), and 1.65 (1.38 to 1.97) in men, and 1.64 (1.42 to 1.89), 3.15 (2.61 to 3.80), and 2.29 (1.82 to 2.89) in women, respectively. In conclusion, blood pressure is more closely related with intracerebral hemorrhage than subarachnoid hemorrhage, thus proportion of intracerebral hemorrhage in hemorrhagic stroke may affect the association between blood pressure and hemorrhagic stroke. Our data also emphasize the importance of blood pressure control for the prevention of stroke, especially in countries with a high incidence of intracerebral hemorrhage.
Inhibition of Rho-Kinase in the Nucleus Tractus Solitarius Enhances Glutamate Sensitivity in Rats
Authors: Ito Koji , Hirooka Yoshitaka , Hori Nobuaki , Kimura Yoshikuni , Sagara Yoji , Shimokawa Hiroaki , Takeshita Akira , Sunagawa Kenji
Published: July 2005

The Rho/Rho–kinase pathway in the central nervous system is involved in the maintenance of dendritic spines, which form the postsynaptic contact sites of excitatory synapses. Inhibition of the Rho–kinase pathway in neuron promotes dendritic spines or branches. In contrast, activation of the Rho/Rho–kinase pathway reduces dendritic spines or branches. Recent studies suggest that morphological changes of dendritic spines occur rapidly, and spine morphology is associated with glutamate sensitivity. The aim of the present study was to determine whether Rho-kinase activity affects glutamate sensitivity in the nucleus tractus solitarii (NTS) of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). We first examined the effects of unilateral glutamate injection in the NTS. There was a significantly smaller decrease in arterial pressure in SHR than in WKY. We then examined the depressor responses evoked by unilateral glutamate injection into the NTS after preinjection of Y-27632, a specific Rho-kinase inhibitor. Preinjection of Y-27632 enhanced the glutamate response in both strains. However, the magnitude of the augmentation was significantly greater in SHR than in WKY. Furthermore, we recorded single-unit activity of NTS neurons from medulla brain slice preparations.
N
-methyl-
d
-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was applied iontophoretically to the recorded neurons, and neuronal activity was recorded before and after Y-27632 perfusion. Y-27632 perfusion increased the response to NMDA and AMPA. These results suggest that inhibition of Rho-kinase activity in the NTS enhances glutamate sensitivity in WKY and SHR and might improve impaired glutamate sensitivity in SHR.
Muscle Sympathetic Nerve Activity Averaged Over 1 Minute Parallels Renal and Cardiac Sympathetic Nerve Activity in Response to a Forced Baroreceptor Pressure Change
Authors: Kamiya Atsunori , Kawada Toru , Yamamoto Kenta , Michikami Daisaku , Ariumi Hideto , Miyamoto Tadayoshi , Uemura Kazunori , Sugimachi Masaru , Sunagawa Kenji
Published: July 2005

Background—

Despite the accumulated knowledge of human muscle sympathetic nerve activity (SNA) as measured by microneurography, whether muscle SNA parallels renal and cardiac SNAs remains unknown.

Method and Results—

In experiment 1, muscle (microneurography, tibial nerve), renal, and cardiac SNAs were recorded in anesthetized rabbits (n=6) while arterial pressure was changed by intravenous bolus injections of nitroprusside (3 μg/kg) followed by phenylephrine (3 μg/kg). In experiment 2, the carotid sinus region was vascularly isolated in anesthetized, vagotomized, and aorta-denervated rabbits (n=10). The 3 SNAs were recorded while intracarotid sinus pressure was increased stepwise from 40 to 160 mm Hg in 20-mm Hg increments maintained for 60 seconds each. Muscle SNA averaged over 1 minute was well correlated with renal (
r
=0.96±0.01, mean±SE) and cardiac (
r
=0.96±0.01) SNAs in experiment 1 (baroreflex closed-loop condition) and also with renal (
r
=0.97±0.01) and cardiac (
r
=0.97±0.01) SNAs in experiment 2 (baroreflex open-loop condition).

Conclusions—

Muscle SNA averaged over 1 minute parallels renal and cardiac SNAs in response to a forced baroreceptor pressure change.
Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness
Authors: Klotz Stefan , Foronjy Robert F. , Dickstein Marc L. , Gu Anguo , Garrelds Ingrid M. , Jan Danser A.H. , Oz Mehmet C. , D’Armiento Jeanine , Burkhoff Daniel
Published: July 2005

Background—

Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown.

Methods and Results—

Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145±33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (
P
<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (
P
<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM.

Conclusions—

LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1–to–TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.
Effect of Pravastatin on Rate of Kidney Function Loss in People With or at Risk for Coronary Disease
Authors: Tonelli Marcello , Isles Chris , Craven Timothy , Tonkin Andrew , Pfeffer Marc A. , Shepherd James , Sacks Frank M. , Furberg Curt , Cobbe Stuart M. , Simes John , West Malcolm , Packard Chris , Curhan Gary C.
Published: July 2005

Background—

Limited data suggest that HMG-CoA reductase inhibitors (statins) reduce rates of kidney function loss. We performed this analysis to determine whether pravastatin reduced the rate of kidney function loss over ≈5 years in people with or at high risk for coronary disease.

Methods and Results—

This was a post hoc subgroup analysis of data from 3 randomized double-blind controlled trials comparing pravastatin 40 mg/d and placebo in subjects with a previous acute coronary syndrome or who were at high cardiovascular risk. The primary outcome was the rate of change in estimated glomerular filtration rate (GFR; in mL/min per 1.73 m
2
/y). The Modified Diet and Renal Disease Study (MDRD) and Cockcroft-Gault equations were used to estimate GFR. We studied 18 569 participants, 3402 (18.3%) of whom had moderate chronic kidney disease as defined by an estimated GFR of 30 to 59.9 mL/min per 1.73 m
2
body surface area. In subjects with moderate chronic kidney disease at baseline, pravastatin reduced the adjusted rate of kidney function loss by ≈34%, although the absolute reduction in the rate of loss was small (0.22 mL/min per 1.73 m
2
/y by MDRD-GFR; 95% CI, 0.07 to 0.37). Pravastatin did not reduce the frequency of ≥25% decreases in kidney function in this group when MDRD-GFR was used to estimate GFR (relative risk [RR], 0.84; 95% CI, 0.66 to 1.06). When all 18 569 subjects were considered, pravastatin reduced the adjusted rate of kidney function loss by 8% (0.08 mL/min per 1.73 m
2
/y by MDRD-GFR; 95% CI, 0.01 to 0.15) and the risk of acute renal failure (RR, 0.60; 95% CI, 0.41 to 0.86) but did not significantly reduce the frequency of a ≥25% decline in kidney function by MDRD-GFR (RR, 0.94; 95% CI, 0.88 to 1.01).

Conclusions—

Pravastatin modestly reduced the rate of kidney function loss in people with or at risk for cardiovascular disease. However, the primary indication for the use of statins in people with or at risk for coronary events remains the reduction in mortality that results from their use.
Metalloproteinase-2 and -9 in Giant Cell Arteritis
Authors: Rodríguez-Pla Alicia , Bosch-Gil Josep A. , Rosselló-Urgell José , Huguet-Redecilla Pere , Stone John H. , Vilardell-Tarres Miquel
Published: July 2005

Background—

Both matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) have been postulated to play roles in the pathophysiology of giant cell arteritis (GCA) because of their ability to degrade elastin. Understanding the specific mediators of arterial damage in GCA could lead to new therapeutic targets in this disease.

Methods and Results—

Temporal artery biopsy specimens were obtained from 147 consecutive patients suspected of GCA. Clinical and histopathological data were collected according to protocol. Using immunohistochemistry, we compared the expression of MMP-2 and MMP-9 in the temporal artery biopsies of both GCA cases (n=50) and controls (n=97). MMP-9 was found more frequently in positive than in negative temporal artery biopsies (adjusted odds ratio [OR], 3.20;
P
=0.01). In contrast, the frequency of MMP-2 was not significantly different between positive and negative biopsies (adjusted OR, 2.18;
P
=0.22). Both MMP-2 and MMP-9 were found in macrophages and giant cells near the internal elastic lamina and in smooth muscle cells and myofibroblasts of the media and intima. MMP-9 was also found in the vasa vasorum. MMP-9 but not MMP-2 was associated with internal elastic lamina degeneration, intimal hyperplasia, and luminal narrowing, even after adjustment for possible confounding variables.

Conclusions—

MMP-9 appears more likely than MMP-2 to be involved in the pathophysiology of GCA. MMP-9 not only participates in the degradation of elastic tissue but also is associated with intimal hyperplasia, subsequent luminal narrowing, and neoangiogenesis. The expression of MMP by smooth muscle cells implicates these cells as potential secretory cells in GCA.
Sudden Unexplained Death
Authors: Tan Hanno L. , Hofman Nynke , van Langen Irene M. , van der Wal Allard C. , Wilde Arthur A.M.
Published: July 2005

Background—

Sudden death mostly follows from cardiac disorders that elicit lethal ventricular arrhythmias. In young individuals, it often remains unexplained because history and/or postmortem analysis are absent or provide no clue. Because such sudden unexplained deaths (SUDs) may have heritable causes, cardiological and genetic assessment of surviving relatives of SUD victims may reveal the underlying disease and unmask presymptomatic carriers. We aimed to establish the diagnostic yield of such assessments.

Methods and Results—

We investigated 43 consecutive families with ≥1 SUD victim who died at ≤40 years of age. All studied relatives underwent resting/exercise ECG and Doppler echocardiography. Molecular genetic analysis was conducted to confirm the diagnosis. We identified an inherited disease and likely cause of death in 17 of 43 families (40%). Twelve families had primary electrical disease: catecholaminergic polymorphic ventricular tachycardia (5 families), long-QT syndrome (4 families), Brugada syndrome (2 families), and long-QT/Brugada syndrome (1 family). Furthermore, we found arrhythmogenic right ventricular cardiomyopathy (3 families), hypertrophic cardiomyopathy (1 family), and familial hypercholesterolemia (1 family). Molecular genetic analysis provided confirmation in 10 families. Finding the diagnosis was more likely when more relatives were examined and in families with ≥2 SUD victims ≤40 years of age. The resting/exercise ECG had a high diagnostic yield. These efforts unmasked 151 presymptomatic disease carriers (8.9 per family).

Conclusions—

Examination of relatives of young SUD victims has a high diagnostic yield, with identification of the disease in 40% of families and 8.9 presymptomatic carriers per family. Simple procedures (examining many relatives) and routine tests (resting/exercise ECG) constitute excellent diagnostic strategies. Molecular genetics provide strong supportive information.
Efferent Vagal Nerve Stimulation Protects Heart Against Ischemia-Induced Arrhythmias by Preserving Connexin43 Protein
Authors: Ando Motonori , Katare Rajesh G. , Kakinuma Yoshihiko , Zhang Dongmei , Yamasaki Fumiyasu , Muramoto Kazuyo , Sato Takayuki
Published: July 2005

Background—

Myocardial ischemia (MI) leads to derangements in cellular electrical stability and the generation of lethal arrhythmias. Vagal nerve stimulation has been postulated to contribute to the antifibrillatory effect. Here, we suggest a novel mechanism for the antiarrhythmogenic properties of vagal stimulation during acute MI.

Methods and Results—

Under anesthesia, Wistar rats underwent 30 minutes of left coronary artery (LCA) ligation with vagal stimulation (MI-VS group, n=11) and with sham stimulation (MI-SS group, n=12). Eight of the 12 rats in the MI-SS group had ventricular tachyarrhythmia (VT) during 30-minute LCA ligation; on the other hand, VT occurred in only 1 of the 11 rats in the MI-VS group (67% versus 9%, respectively). Atropine administration abolished the antiarrhythmogenic effect of vagal stimulation. Immunoblotting revealed that the MI-SS group showed a marked reduction in the amount of phosphorylated connexin43 (Cx43), whereas the MI-VS group showed only a slight reduction compared with the sham operation and sham stimulation group (37±20% versus 79±18%). Immunohistochemistry confirmed that the MI-induced loss of Cx43 from intercellular junctions was prevented by vagal stimulation. In addition, studies with rat primary-cultured cardiomyocytes demonstrated that acetylcholine effectively prevented the hypoxia-induced loss of phosphorylated Cx43 and ameliorated the loss of cell-to-cell communication as determined by Lucifer Yellow dye transfer assay, which supports the in vivo results.

Conclusions—

Vagal nerve stimulation exerts antiarrhythmogenic effects accompanied by prevention of the loss of phosphorylated Cx43 during acute MI and thus plays a critical role in improving ischemia-induced electrical instability.
Allogeneic Mesenchymal Stem Cell Transplantation in Postinfarcted Rat Myocardium
Authors: Dai Wangde , Hale Sharon L. , Martin Bradley J. , Kuang Jin-Qiang , Dow Joan S. , Wold Loren E. , Kloner Robert A.
Published: July 2005

Background—

Mesenchymal stem cells (MSCs) have the potential to replace infarct scar, but the long-term effects are unknown. We studied short- and long-term effects of MSC transplantation on left ventricular (LV) function in a rat myocardial infarction model.

Methods and Results—

Saline (n=46) or MSCs labeled with 1,1′-dioctadecyl-3,3,3′3′-testramethylindocarbocyanine perchlorate (DiI; n=49, 2×10
6
cells each) were injected into the scar of a 1-week-old myocardial infarction in Fischer rats. The presence and differentiation of engrafted cells and their effect on LV ejection fraction was assessed. At 4 weeks, LV stroke volume was significantly greater in the MSC-treated group (145±9 μL) than in the saline group (122±3 μL,
P
=0.032), and LV ejection fraction was significantly greater in MSC-treated animals (43.8±1.0%) than in the saline group (38.8±1.1%,
P
=0.0027). However, at 6 months, these benefits of MSC treatment were lost. DiI-positive cells were observed in the MSC group at 2 weeks and at 3 and 6 months. Expression of the muscle-specific markers α-actinin, myosin heavy chain, phospholamban, and tropomyosin was not observed at 2 weeks in DiI-positive cells. At 3 and 6 months, the DiI-positive cells were observed to express the above muscle-specific markers, but they did not fully evolve into an adult cardiac phenotype. Some of the DiI-positive cells expressed von Willebrand factor.

Conclusions—

Allogeneic MSCs survive in infarcted myocardium as long as 6 months and express markers that suggest muscle and endothelium phenotypes. MSCs improved global LV function at 4 weeks; however, this benefit was transient, which suggests a possible early paracrine effect.
Heritability and a Genome-Wide Linkage Scan for Arterial Stiffness, Wave Reflection, and Mean Arterial Pressure
Authors: Mitchell Gary F. , DeStefano Anita L. , Larson Martin G. , Benjamin Emelia J. , Chen Ming-Huei , Vasan Ramachandran S. , Vita Joseph A. , Levy Daniel
Published: July 2005

Background—

Arterial stiffness and mean arterial pressure variably contribute to systolic hypertension and increased cardiovascular risk. However, few prior community-based studies have evaluated the genetics of arterial stiffness and separate mean and pulsatile components of blood pressure.

Methods and Results—

Using arterial tonometry, we evaluated heritability and linkage of forward and reflected wave amplitude, mean arterial pressure, and carotid-femoral pulse wave velocity (CFPWV) in 1480 participants representing 817 pedigrees in the Framingham Study offspring cohort. In 204 families with tonometry data, a genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals. Heritability estimates were moderate for reflected wave amplitude (h
2
=0.48), forward wave amplitude (h
2
=0.21), CFPWV (h
2
=0.40), and mean arterial pressure (h
2
=0.33). Variance components linkage analysis identified 2 regions of linkage for reflected wave amplitude: chromosome 4 at 181 cM (logarithm of odds [LOD]=4.93, permuted
P
=0.002) and chromosome 8 at 33 cM (LOD=3.27, permuted
P
=0.058). There was 1 region of linkage for forward wave amplitude on chromosome 7 at 174 cM (LOD=2.88, permuted
P
=0.017). There were several regions of suggestive linkage for CFPWV: chromosome 2 at 94 cM (LOD=2.46), chromosome 7 at 29 cM (LOD=2.50), chromosome 13 at 108 cm (LOD=2.10), and chromosome 15 at 108 cM (LOD=2.48). There was 1 region of suggestive linkage for mean arterial pressure on chromosome 1 at 192 cM (LOD=2.18).

Conclusions—

Arterial stiffness measures and mean and pulsatile components of blood pressure are heritable and appear to have genetic determinants that may be linked to separate genetic loci in humans.
L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation
Authors: Hannawa Kevin K. , Eliason Jonathan L. , Woodrum Derek T. , Pearce Charles G. , Roelofs Karen J. , Grigoryants Vladimir , Eagleton Matthew J. , Henke Peter K. , Wakefield Thomas W. , Myers Daniel D. , Stanley James C. , Upchurch Gilbert R.
Published: July 2005

Background—This investigation tested the hypothesis that L-selectin is important in experimental abdominal aortic aneurysm (AAA) formation in rodents.

Methods and Results—Rat abdominal aortas were perfused with saline (control) or porcine pancreatic elastase and studied on postperfusion days 1, 2, 4, 7, and 14 (n=5 per treatment group per day). Neutrophil (polymorphonucleur leukocyte, PMN) and macrophage counts per high-powered field (HPF) were performed on fixed sections. L-selectin expression and protein levels in aortic tissue were determined by polymerase chain reaction and Western blot, respectively. Elastase-perfused aortic diameters were significantly increased compared with control aortas at all time points except day 1 (P<0.05). PMN counts significantly increased in elastase-perfused aortas compared with control aortas at days 1, 2, and 4, reaching maximum levels at day 7 (40.8 versus 0.3 PMNs/HPF,P=0.001). L-selectin mRNA expression in elastase-perfused aortas was 18 (P=0.018), 17 (P<0.001), and 8 times (P=0.02) times greater than control aortas at days 1, 2, and 4, respectively. Western blot demonstrated a significant 69% increase in L-selectin protein at day 7 in elastase- as compared with saline-perfused aortas (P=0.005). Subsequent experiments involved similar studies on postperfusion days 4, 7, and 14 of aortas from C57BL/6 wild-type (WT) mice (n=21) and L-selectin–knockout (LKO) mice (n=19). LKO mice had significantly smaller aortic diameters at day 14 as compared with WT mice (88% versus 123%,P=0.02). PMN counts were significantly greater in elastase-perfused WT mouse aortas as compared with LKO mouse aortas at day 4 after perfusion (12.8 versus 4.8 PMNs/HPF,P=0.02). Macrophage counts were significantly greater at all time points after perfusion in elastase-perfused WT mouse aortas compared with elastase-perfused LKO mouse aortas, with a maximum difference at day 7 after perfusion (13.3 versus 0.5 macrophages/HPF,P<0.001).

Conclusion—L-selectin–mediated neutrophil recruitment may be a critical early step in AAA formation.
Revolution or Self-Defense? Communist Goals, Strategy, and Tactics in the Greek Civil War
Authors: Iatrides John O.
Published: July 2005

At the end of World War II the Greek Communist party (KKE) claimed that it would seek an accommodation with its domestic opponents, but the party soon launched a full-scale insurrection on its own initiative in the expectation of receiving decisive support from the Soviet Union.With civil war under way, the head of the KKE, Nikos Zahariadis, repeatedly told Soviet of ficials that victory was certain if the Greek Communists could obtain funding, weapons, and other equipment from the USSR and its allies.Although Soviet leaders were concerned that the KKE's aggressiveness would provoke a U.S. reaction, they permitted the clandestine shipment of large quantities of supplies that delayed but could not avert the insurgents'defeat.U.S.of ficials at the time largely misperceived the causes of the insurrection, but they correctly sensed that the KKE's dependence on Soviet-bloc assistance would ensure that a Communist victory would bring Greece into Moscow's orbit.
The Nixon Administration, the “Horror Strategy,” and the Search for Limited Nuclear Options, 1969–1972
Authors: Burr William
Published: July 2005

In early 1969 President Richard Nixon and his national security adviser, Henry Kissinger, received a brie fing on the U.S.nuclear war plan, the Single Integrated Operational Plan (SIOP). Appalled by the catastrophic scale of the SIOP, Nixon and Kissinger sought military options that were more credible than massive nuclear strikes. Participants in the Air Force Nuclear Options project also supported more flexible nuclear war plans.Although Kissinger repeatedly asked Defense Department of ficials to construct limited options, they were skeptical that it would be possible to control nuclear escalation or to introduce greater flexibility without weakening the SIOP.Interagency studies presented a mixed verdict about the desirability of limited options; nevertheless, continued White House pressure encouraged Secretary of Defense Melvin Laird to sponsor a major review of nuclear targeting.In 1972 the Foster panel developed concepts of limited, selective, and regional nuclear options that were responsive to Kissinger's interest in credible nuclear threats. The Foster panel's report led to the controversial “Schlesinger Doctrine” and further efforts to revise the SIOP, but serious questions endured about the whole concept of controlled nuclear warfare.
Continuity and Change Reinterpreting the Policies of the Truman and Eisenhower Administrations toward Iran, 1950–1954
Authors: Marsh Steve
Published: July 2005

It has long been argued that the Eisenhower administration pursued a more assertive policy toward Iran than the Truman administration did.This interpretative consensus, though, has recently come under challenge.In the Journal of Cold War Studies in 1999, Francis Gavin argued that U.S.policy toward Iran in 1950–1953 became progressively more assertive in response to a gradual shift in the global U.S. -USSR balance of power.This article shares, and develops further, Gavin's revisionist theme of policy continuity, but it explains the continuity by showing that Truman and Eisenhower had the same principal objectives and made the same basic assumptions when devising policy. The more assertive policy was primarily the result of the failure of U.S. policy by early 1952. The Truman administration subsequently adopted a more forceful policy, which Eisenhower simply continued until all perceived options for saving Iran from Communism were foreclosed other than that of instigating a coup to bring about a more pliable government.
Generalized and Specific Attachment Representations: Unique and Interactive Roles in Predicting Conflict Behaviors in Close Relationships
Authors: Creasey Gary , Ladd Aimee
Published: July 2005

The authors expected that associations between the representations individuals possess regarding romantic partners and their conflict behavior would be moderated by generalized attachment representations (GAR). To test this premise, college students (N =130) were administered two attachment measures and were observed during conflict negotiation with their partners. The Relationship Styles Questionnaire assessed specific representations regarding partners and GAR were measured by the Adult Attachment Interview. The relationship between romantic partner representations and conflict tactics were dependent on GAR. Individuals who possessed secure GAR generally displayed good conflict management skills, regardless of their attachment representations regarding their romantic partners. Individuals who held more anxious or avoidant perceptions of romantic partners displayed more problematic conflict tactics if they possessed insecure GAR; however, these associations were dependent on the type of conflict behavior and the type of insecure GAR. Implications for future research are discussed.
It’s a Bet! A Problem-Solving Approach Promotes the Construction of Contingent Agreements
Authors: Kray Laura J. , Thompson Leigh , Lind E. Allan
Published: July 2005

Negotiators often have different expectations about the future. A contingent agreement, or a bet that makes the ultimate outcome dependent on some future event, builds on negotiators’ differences. The authors argue that a problem-solving approach, in which negotiators thorougly explore options to build on their differences, is most likely to construct contingent agreements. The authors explore two factors expected to influence this problem-solving approach, namely, negotiators’ relational and accountability concerns. The authors argue when these considerations are imbalanced, negotiators are less likely to adopt a problem-solving style and construct a contingent agreement. To test this hypothesis, negotiators’ relationships and accountability pressures were manipulated in two experiments. In Experiment 1, participants engaged in an integrative negotiation, allowing the authors to examine whether a contingent agreement was constructed and joint gain. Experiment 2 sought to replicate and extend the findings of Experiment 1 using a scenario study. Results across the two experiments support the authors’ hypotheses.
Regulatory Focus at the Bargaining Table: Promoting Distributive and Integrative Success
Authors: Galinsky Adam D. , Leonardelli Geoffrey J. , Okhuysen Gerardo A. , Mussweiler Thomas
Published: July 2005

The authors demonstrate that in dyadic negotiations, negotiators with a promotion regulatory focus achieve superior outcomes than negotiators with prevention regulatory focus in two ways. First, a promotion focus leads negotiators to claim more resources at the bargaining table. In the first two studies, promotion-focused negotiators paid more attention to their target prices(i.e., their ideal outcomes) and achieved more advantageous distributive outcomes than did prevention-focused negotiators. The second study also reveals an important mediating process: Negotiators with a promotion focus made more extreme opening offers in their favor. Second, a promotion focus leads negotiators to create more resources at the bargaining table that benefit both parties. A third study demonstrated that in a multi-issue negotiation, a promotion focus increased the likelihood that a dyad achieved a jointly optimal or Pareto efficient outcome compared to prevention-focused dyads. The discussion focuses on the role of regulatory focus in social interaction and introduces the notion of interaction fit.
Humanized anti–interleukin-6 receptor antibody treatment of multicentric Castleman disease
Authors: Nishimoto Norihiro , Kanakura Yuzuru , Aozasa Katsuyuki , Johkoh Takeshi , Nakamura Minoru , Nakano Shuji , Nakano Nobuaki , Ikeda Yasuo , Sasaki Takeshi , Nishioka Kiyoshi , Hara Masamichi , Taguchi Hirokuni , Kimura Yukihiko , Kato Yoshiro , Asaoku Hideki , Kumagai Shunichi , Kodama Fumio , Nakahara Hideko , Hagihara Keisuke , Yoshizaki Kazuyuki , Kishimoto Tadamitsu
Published: July 2005

Multicentric Castleman disease (MCD) is an atypical lymphoproliferative disorder characterized by systemic lymphadenopathy and constitutional inflammatory symptoms. Dysregulated overproduction of interleukin-6 is responsible for the clinical abnormalities. This multicenter prospective study was undertaken to evaluate the safety and efficacy of a humanized anti–human interleukin-6 (IL-6) receptor monoclonal antibody (MRA) in patients with MCD. We report here results of the first 60 weeks of the study enrolling 28 patients. The initial dosing period consisted of 8 infusions of 8 mg/kg MRA administered biweekly. Adjustments in the dose and treatment interval were allowed for each patient in an extension phase after 16 weeks. Within 16 weeks, treatment with MRA consistently alleviated lymphadenopathy and all the inflammatory parameters. Hemoglobin, albumin, and total cholesterol levels, high-density lipoprotein cholesterol values, and body mass index all increased significantly. In addition, fatigue diminished. Chronic inflammatory symptoms were successfully managed over 60 weeks. In 8 (28.6%) patients, the MRA dose was decreased or the treatment interval was extended without exacerbation. Eleven (73.3%) of 15 patients who had received oral corticosteroids before study entry were able to do well on a reduced corticosteroid dose. Most adverse events were mild to moderate in severity. MRA was tolerated well and significantly alleviated chronic inflammatory symptoms and wasting in patients with MCD.
An alternative exon 1 of the CD5 gene regulates CD5 expression in human B lymphocytes
Authors: Renaudineau Yves , Hillion Sophie , Saraux Alain , Mageed Rizgar A. , Youinou Pierre
Published: July 2005

T lymphocytes and a subpopulation of B lymphocytes express the CD5 coreceptor. Its functional importance is evident from the multiple levels and developmental stages of the regulation of its expression. We here report the discovery of a novel regulatory exon upstream of the noncoding region of the CD5 gene in humans. This alternate exon 1 is designated E1B (with the conventional exon 1 renamed E1A) and was shown to regulate the expression of CD5. E1B-containing transcripts existed exclusively in B lymphocytes and encoded a protein that was truncated and retained intracellularly. As a consequence, the amount of E1A-containing transcripts was down-regulated and the membrane CD5 expression was diminished in the presence of E1B-containing transcripts. High levels of E1A transcripts were found in chronic lymphocytic leukemia, and there were no E1A transcripts in 697 pre-B cells, which have no membrane CD5. Introduction of E1B into Jurkat cells reduced their membrane expression of CD5, and sequence analysis revealed that the E1B motif is a defective human endogenous retrovirus. A balance between the 2 alternative exons 1 might be central to the regulation of membrane CD5 in human B cells, and, through CD5-associated SH2-containing phosphatase 1, to the modulation of B-cell antigen receptor-transduced signals.
Quiescent and activated mouse granulocytes do not express granzyme A and B or perforin: similarities or differences with human polymorphonuclear leukocytes?
Authors: Martin Praxedis , Wallich Reinhard , Pardo Julian , Müllbacher Arno , Munder Markus , Modolell Manuel , Simon Markus M.
Published: July 2005

Polymorphonuclear leukocytes have been shown to use a multitude of effector functions to combat pathogens and tumors, including enzymes, defensins, and toxic products such as oxygen radicals and nitrogen oxides. Recent studies provided evidence for the expression of granzymes (gzms) and perforin (perf) within the cytotoxic arsenal of human neutrophils, the validity of which was questioned by 2 subsequent studies. We have now used cytology, intracellular flow cytometry, enzymatic assays, immunoelectron microscopy, and quantitative reverse transcriptase-polymerase chain reaction to obtain evidence of the presence of gzms and/or perf in mouse Gr-1+ granulocyte populations. The data obtained clearly demonstrate that neither in vitro- nor in vivo-derived mouse granulocytes synthesize gzmA and gzmB or perf, even following infection/immunization with pathogens or pathogen-derived material. A parallel comparable analysis on the expression of gzmB in human neutrophils from 3 healthy control subjects and 4 patients with diverse diseases failed to detect gzmB expression. The data indicate that polymorphonuclear leukocytes from mice and humans lack the 3 cytotoxic effector molecules, gzmA, gzmB, and perf, generally associated with natural killer and cytotoxic T lymphocytes. (Blood. 2005;106:2871-2878)
Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin
Authors: Lin Lan , Goldberg Y. Paul , Ganz Tomas
Published: July 2005

Mutations in a recently identified gene HJV (also called HFE2, or repulsive guidance molecule C, RgmC) are the major cause of juvenile hemochromatosis (JH). The protein product of HJV, hemojuvelin, contains a C-terminal glycosylphosphatidylinositol anchor, suggesting that it can be present in either a soluble or a cell-associated form. Patients with HJV hemochromatosis have low urinary levels of hepcidin, the principal iron-regulatory hormone secreted by the liver. However, neither the specific role of hemojuvelin in maintaining iron homeostasis nor its relationship to hepcidin has been experimentally established. In this study we used hemojuvelin-specific siRNAs to vary hemojuvelin mRNA concentration and showed that cellular hemojuvelin positively regulated hepcidin mRNA expression, independently of the interleukin 6 pathway. We also showed that recombinant soluble hemojuvelin (rs-hemojuvelin) suppressed hepcidin mRNA expression in primary human hepatocytes in a log-linear dose-dependent manner, suggesting binding competition between soluble and cell-associated hemojuvelin. Soluble hemojuvelin was found in human sera at concentrations similar to those required to suppress hepcidin mRNA in vitro. In cells engineered to express hemojuvelin, soluble hemojuvelin release was progressively inhibited by increasing iron concentrations. We propose that soluble and cell-associated hemojuvelin reciprocally regulate hepcidin expression in response to changes in extracellular iron concentration. (Blood. 2005;106:2884-2889)
An in vivo analysis of the localisation and interactions of human p66 DNA polymerase δ subunit
Authors: Pohler J Richard G , Otterlei Marit , Warbrick Emma
Published: July 2005

Background

DNA polymerase δ is essential for eukaryotic DNA replication and also plays a role in DNA repair. The processivity of this polymerase complex is dependent upon its interaction with the sliding clamp PCNA and the polymerase-PCNA interaction is largely mediated through the p66 polymerase subunit. We have analysed the interactions of the human p66 DNA polymerase δ subunit with PCNA and with components of the DNA polymerase δ complexin vivo.

Results

Using the two-hybrid system, we have mapped the interaction domains for binding to the p50 polymerase δ subunit and with PCNA to the N-terminus and the C-terminus of p66, respectively. Co-immunoprecipitation experiments confirm that these interaction domains are functionalin vivo. Expression of EGFP-p66 shows that it is a nuclear protein which co-localises with PCNA throughout the cell cycle. p66 is localised to sites of DNA replication during S phase and to repair foci following DNA damage. We have identified a functional nuclear localisation sequence and shown that localisation to replication foci is not dependent upon active nuclear import. Sub-domains of p66 act as dominant negative suppressors of colony formation, suggesting that p66 forms an essential structural link between the p50 subunit and PCNA. Analysis of the C-terminal PCNA binding motif shows that deletion of the QVSITGFF core motif results in a reduced affinity for PCNA, while deletion of a further 20 amino acids completely abolishes the interaction. A reduced affinity for PCNA correlates with reduced targeting to replication foci. We have confirmed the p66-PCNA interactionin vivousing fluorescence resonance energy transfer (FRET) techniques.

Conclusion

We have defined the regions of p66 required for its interaction with PCNA and the p50 polymerase subunit. We demonstrate a functional link between PCNA interaction and localisation to replication foci and show that there is a direct interaction between p66 and PCNA in living cells during DNA replication. The dominant negative effect upon growth resulting from expression of p66 sub-domains confirms that the p66-PCNA interaction is essentialin vivo.
A randomized, controlled trial of spinal endoscopic adhesiolysis in chronic refractory low back and lower extremity pain [ISRCTN 16558617]
Authors: Manchikanti Laxmaiah , Boswell Mark V , Rivera Jose J , Pampati Vidya Sagar , Damron Kim S , McManus Carla D , Brandon Doris E , Wilson Sue R
Published: July 2005

Background

Postoperative epidural fibrosis may contribute to between 5% to 60% of the poor surgical outcomes following decompressive surgery. Correlations have been reported between epidural scarring and radicular pain, poor surgical outcomes, and a lack of any form of surgical treatment. The use of spinal endoscopic adhesiolysis in recent years in the management of chronic refractory low back and lower extremity pain has been described.

Methods

A prospective, randomized, double-blind trial was conducted to determine the outcome of spinal endoscopic adhesiolysis to reduce pain and improve function and psychological status in patients with chronic refractory low back and lower extremity pain. A total of 83 patients were evaluated, with 33 patients in Group I and 50 patients in Group II. Group I served as the control, with endoscopy into the sacral level without adhesiolysis, followed by injection of local anesthetic and steroid. Group II received spinal endoscopic adhesiolysis, followed by injection of local anesthetic and steroid.

Results

Among the 50 patients in the treatment group receiving spinal endoscopic adhesiolysis, significant improvement without adverse effects was shown in 80% at 3 months, 56% at 6 months, and 48% at 12 months. The control group showed improvement in 33% of the patients at one month and none thereafter. Based on the definition that less than 6 months of relief is considered short-term and longer than 6 months of relief is considered long-term, a significant number of patients obtained long-term relief with improvement in pain, functional status, and psychological status.

Conclusion

Spinal endoscopic adhesiolysis with targeted delivery of local anesthetic and steroid is an effective treatment in a significant number of patients with chronic low back and lower extremity pain without major adverse effects.