bluuebunny/crossref_metadata_2025 huggingface dataset:
M-wave properties during progressive motor unit activation by transcutaneous stimulation
Authors: Farina Dario , Blanchietti Andrea , Pozzo Marco , Merletti Roberto
Published: May 2004

The aim of this study was to interpret changes in experimentally recorded M waves with progressive motor unit (MU) activation based on simulation of the surface electromyogram. Activation order during transcutaneous electrical stimulation was analyzed by investigating M-wave average rectified value, spectral properties, and conduction velocity (CV) during electrically elicited contractions. M-waves were detected from the biceps brachii muscle of 10 healthy male subjects by a linear adhesive array of eight electrodes. Electrical stimulation was delivered to the motor point at either constant current intensity (40, 60, 80, and 100% of the supramaximal stimulation current) or with linearly increasing current. A model of surface electromyogram generation that varied activation order based on MU size and location was used to interpret the experimental results. From the experimental and model analysis, it was found that 1) MUs tended to be activated from low to high CV and from the superficial to the deep muscle layers with increasing transcutaneous electrical stimulation of the biceps brachii muscle, and 2) characteristic spectral frequencies of the M-wave were affected by many factors other than average CV (such as the activation order by MU location or the spread of the MU innervation zones and CVs), thus decreasing with a concomitant increase in CV during progressive MU activation.
Does exercise-induced hypoxemia modify lactate influx into erythrocytes and hemorheological parameters in athletes?
Authors: Connes Philippe , Bouix Didier , Py Guillaume , Caillaud Corinne , Kippelen Pascale , Brun Jean-Frédéric , Varray Alain , Prefaut Christian , Mercier Jacques
Published: May 2004

This study investigated 1) red blood cells (RBC) rigidity and 2) lactate influxes into RBCs in endurance-trained athletes with and without exercise-induced hypoxemia (EIH). Nine EIH and six non-EIH subjects performed a submaximal steady-state exercise on a cyclo-ergometer at 60% of maximal aerobic power for 10 min, followed by 15 min at 85% of maximal aerobic power. At rest and at the end of exercise, arterialized blood was sampled for analysis of arterialized pressure in oxygen, and venous blood was drawn for analysis of plasma lactate concentrations and hemorheological parameters. Lactate influxes into RBCs were measured at three labeled [U-14C]lactate concentrations (1.6, 8.1, and 41 mM) on venous blood sampled at rest. The EIH subjects had higher maximal oxygen uptake than non-EIH ( P < 0.05). Total lactate influx was significantly higher in RBCs from EIH compared with non-EIH subjects at 8.1 mM (1,498.1 ± 87.8 vs. 1,035.9 ± 114.8 nmol·ml−1·min−1; P < 0.05) and 41 mM (2,562.0 ± 145.0 vs. 1,618.1 ± 149.4 nmol·ml−1·min−1; P < 0.01). Monocarboxylate transporter-1-mediated lactate influx was also higher in EIH at 8.1 mM ( P < 0.05) and 41 mM ( P < 0.01). The drop in arterial oxygen partial pressure was negatively correlated with total lactate influx measured at 8.1 mM ( r = −0.82, P < 0.05) and 41 mM ( r = −0.84, P < 0.05) in the two groups together. Plasma lactate concentrations and hemorheological data were similar in the two groups at rest and at the end of exercise. The results showed higher monocarboxylate transporter-1-mediated lactate influx in the EIH subjects and suggested that EIH could modify lactate influx into erythrocyte. However, higher lactate influx in EIH subjects was not accompanied by an increase in RBC rigidity.
Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice
Authors: Glaab Thomas , Mitzner Wayne , Braun Armin , Ernst Heinrich , Korolewitz Regina , Hohlfeld Jens M. , Krug Norbert , Hoymann Heinz G.
Published: May 2004

Precise and repeatable measurements of pulmonary function in intact mice are becoming increasingly important for experimental investigations on various respiratory disorders including asthma. Here, we present validation of a novel in vivo method that, for the first time, combines direct and repetitive recordings of standard pulmonary mechanics with cholinergic aerosol challenges in anesthetized, orotracheally intubated, spontaneously breathing mice. We demonstrate that, in several groups of nonsensitized BALB/c mice, dose-related increases in pulmonary resistance and dynamic compliance to aerosolized methacholine are reproducible over short and extended intervals without causing detectable cytological alterations in the bronchoalveolar lavage or relevant histological changes in the proximal trachea and larynx regardless of the number of orotracheal intubations. Moreover, as further validation, we confirm that allergic mice, sensitized and challenged with Aspergillus fumigatus, were significantly more responsive to cholinergic challenge ( P < 0.01) and exhibited marked eosinophilia and lymphocytosis in bronchoalveolar lavage fluids as well as significant pathological alterations in laryngotracheal histology compared with nonsensitized mice. We suggest that this approach will provide useful and necessary information on pulmonary mechanics in studies of various respiratory disorders in mice, including experimental models of asthma and chronic obstructive pulmonary disorder, investigations of pulmonary pharmacology, or more general investigations of the genetic determinants of lung function.
Interindividual variation in abdominal subcutaneous and visceral adipose tissue: influence of measurement site
Authors: Lee SoJung , Janssen Ian , Ross Robert
Published: May 2004

We evaluated the influence of measurement site on the ranking (low to high) of abdominal subcutaneous (SAT) and visceral (VAT) adipose tissue. We also determined the influence of measurement site on the prediction of abdominal SAT and VAT mass. The subjects included 100 men with computed tomography (CT) measurements at L4–L5 and L3–L4 levels and 100 men with magnetic resonance imaging (MRI) measurements at L4–L5 and 5 cm above L4–L5 (L4–L5 +5 cm). Corresponding mass values were determined by using multiple-image protocols. For SAT, 90 and 92 of the 100 subjects for CT and MRI, respectively, had a difference in rank position at the two levels. The change in rank position exceeded the error or measurement for ∼75% of the subjects for both methods. For VAT, 91 and 95 of the 100 subjects for CT and MRI, respectively, had a difference in rank position at the two levels. The change in rank position exceeded the error of measurement for 36% of the subjects for CT and for 8% of the subjects for MRI. For both imaging modalities, the variance explained in SAT and VAT mass (kg) was comparable for L4–L5, L4–L5 +5 cm, and L3–L4 levels. In conclusion, the ranking of subjects for abdominal SAT and VAT quantity is influenced by measurement location. However, the ability to predict SAT and VAT mass by using single images obtained at the L4–L5, L4–L5 +5 cm, or L3–L4 levels is comparable.
Pain Facilitates Tactile Processing in Human Somatosensory Cortices
Authors: Ploner Markus , Pollok Bettina , Schnitzler Alfons
Published: May 2004

Touch and pain are intimately related modalities. Despite a substantial overlap in their cortical representations interactions between both modalities are largely unknown at the cortical level. We therefore used magnetoencephalography and selective nociceptive cutaneous laser stimulation to investigate the effects of brief painful stimuli on cortical processing of touch. Using a conditioning test stimulus paradigm, our results show that painful conditioning stimuli facilitate processing of tactile test stimuli applied 500 ms later. This facilitation applies to cortical responses later than 40 ms originating from primary (S1) and secondary (S2) somatosensory cortices but not to earlier S1 responses. By contrast, tactile conditioning stimuli yield a decrease of early as well as late responses to tactile test stimuli. Control experiments show that pain-induced facilitation of tactile processing is not restricted to the site of the painful conditioning stimulus, whereas auditory conditioning does not yield a comparable facilitation. Apart from a lack of spatial specificity, the facilitating effect of pain closely resembles attentional effects on cortical processing of tactile stimuli. Thus these findings may represent a physiological correlate of an alerting function of pain as a change in the internal state to prepare for processing signals of particular relevance.
Comprehensive transthoracic cardiac imaging in mice using ultrasound biomicroscopy with anatomical confirmation by magnetic resonance imaging
Authors: Zhou Yu-Qing , Foster F. Stuart , Nieman Brian J. , Davidson Lorinda , Chen X. Josette , Henkelman R. Mark
Published: May 2004

High-frequency ultrasound biomicroscopy (UBM) has recently emerged as a high-resolution means of phenotyping genetically altered mice and has great potential to evaluate the cardiac morphology and hemodynamics of mouse mutants. However, there is no standard procedure of in vivo transthoracic cardiac imaging using UBM to comprehensively phenotype the adult mice. In this paper, the characteristic mouse thoracic anatomy is elucidated using magnetic resonance (MR) imaging on fixed mice. Besides the left parasternal and apical windows commonly used for transthoracic ultrasound cardiac imaging, a very useful right parasternal window is found. We present strategies for optimal visualization using UBM of key cardiac structures including: 1) the right atrial inflow channels such as the right superior vena cava; 2) the right ventricular inflow tract via the tricuspid orifice; 3) the right ventricular outflow tract to the main pulmonary artery; 4) the left atrial inflow channel, e.g., pulmonary vein; 5) the left ventricular inflow tract via the mitral orifice; 6) the left ventricular outflow tract to the ascending aorta; 7) the left coronary artery; and 8) the aortic arch and associated branches. Two-dimensional ultrasound images of these cardiac regions are correlated to similar sections in the three-dimensional MR data set to verify anatomical details of the in vivo UBM imaging. Dimensions of the left ventricle and ascending aorta are measured by M-mode. Flow velocities are recorded using Doppler at six representative intracardiac locations: right superior vena cava, tricuspid orifice, main pulmonary artery, pulmonary vein, mitral orifice, and ascending aorta. The methodologies and baseline measurements of inbred mice provide a useful guide for investigators applying the high-frequency ultrasound imaging to mouse cardiac phenotyping.
AIF-1 Expression Modulates Proliferation of Human Vascular Smooth Muscle Cells by Autocrine Expression of G-CSF
Authors: Chen Xing , Kelemen Sheri E. , Autieri Michael V.
Published: May 2004

Objective—

Allograft inflammatory factor-1 (AIF-1) is associated with vascular smooth muscle cell (VSMC) activation and vascular injury. The purpose of this study was to characterize the molecular mechanism of AIF-1 growth-enhancing effects in human VSMC.

Methods and Results—

Primary human VSMCs were stably transduced with AIF-1 retrovirus (RV). Impact on cell growth was evaluated by the increase in cell number, and the effects on gene expression were determined by cDNA microarray analysis. AIF-RV overexpressing cells grew significantly more rapidly than empty-RV control cells in growth medium and serum-reduced medium (
P
<0.01 and 0.02, respectively). cDNA microarray analysis and Western blotting on serum-starved AIF-1–transduced VSMCs identified increased mRNA expression of several cell cycle proteins and, surprisingly, the cytokine G-CSF. Addition of G-CSF caused a 75% increase in proliferation of VSMCs in the absence of serum growth factors. The proliferative effects of AIF-1 were abrogated by neutralizing antibodies to G-CSF (
P
<0.05), and AIF-1–transduced VSMCs are chemotactic for human monocytes. Increased expression of G-CSF and colocalization with AIF-1 positive cells were seen in diseased, not normal human coronary arteries.

Conclusions—

This study indicates that AIF-1 enhances VSMC growth by autocrine production of G-CSF, and AIF-1 expression may influence VSMC–inflammatory cell communication.
Peroxisome Proliferator–Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease
Authors: Tenenbaum Alexander , Motro Michael , Fisman Enrique Z. , Schwammenthal Ehud , Adler Yehuda , Goldenberg Ilan , Leor Jonathan , Boyko Valentina , Mandelzweig Lori , Behar Solomon
Published: May 2004

Background—

Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism. Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of the peroxisome proliferator–activated receptor ligand bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period.

Methods and Results—

The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). The patients received either 400 mg bezafibrate retard (156 patients) or placebo (147 patients) once a day. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. During follow-up, development of new-onset diabetes was recorded in 146 patients: in 80 (54.4%) from the placebo group and 66 (42.3%) from the bezafibrate group (
P
=0.04). The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo: 4.6±2.3 versus 3.8±2.6 years (
P
=0.004). Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development (hazard ratio, 0.70; 95% CI, 0.49 to 0.99). Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level (hazard ratio, 1.22; 95% CI 1.0 to 1.51) and body mass index (hazard ratio, 1.10; 95% CI, 1.05 to 1.16).

Conclusions—

Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination of bezafibrate with other recommended drugs for secondary prevention (statins and ACE inhibitors) would be as efficacious as suggested by our results remains to be determined.
Optimal Noninvasive Assessment of Left Ventricular Filling Pressures
Authors: Dokainish Hisham , Zoghbi William A. , Lakkis Nasser M. , Al-Bakshy Faiz , Dhir Meeney , Quinones Miguel A. , Nagueh Sherif F.
Published: May 2004

Background—

Early transmitral velocity/tissue Doppler mitral annular early diastolic velocity (E/Ea) and B-type natriuretic peptide (BNP) have been correlated with left ventricular filling pressures, yet there are no data on how these 2 estimates of left ventricular filling pressures compare.

Methods and Results—

Patients admitted to intensive care underwent simultaneous tissue Doppler echocardiography, BNP measurement, and pulmonary capillary wedge pressure (PCWP) determination. The ability of mitral E/Ea and BNP to predict PCWP >15 mm Hg was assessed. Fifty patients were studied. Ln BNP had a correlation of
r
=0.32 (
P
=0.02) with PCWP compared with
r
=0.69 (
P
<0.001) between E/Ea and PCWP. E/Ea >15 was the optimal cutoff to predict PCWP >15 mm Hg (sensitivity, 86%; specificity, 88%), whereas the optimal BNP cutoff was >300 pg/mL (sensitivity, 91%; specificity, 56%). The correlation between change in PCWP and change in E/Ea at 48 hours was
r
=0.87 (
P
=0.003) compared with
r
=−0.59 (
P
=0.39) for BNP. In the 36 patients with cardiac disease, E/Ea >15 (sensitivity, 92%; specificity, 91%) appeared more accurate than BNP >400 pg/mL (sensitivity, 92%; specificity, 51%), whereas in patients without cardiac disease, BNP (sensitivity, 81%; specificity, 83%) appeared more accurate than E/Ea >15 (sensitivity, 74%; specificity, 72%) for PCWP >15 mm Hg.

Conclusions—

In intensive care unit patients, mitral E/Ea has a better correlation than BNP with PCWP. Both BNP and mitral E/Ea have high sensitivity for PCWP >15 mm Hg; however, E/Ea appears more specific in this patient population. In patients without cardiac disease, BNP appears more accurate than E/Ea for PCWP >15 mm Hg, whereas E/Ea appears more accurate in patients with cardiac disease.
Short-Acting β-Adrenergic Antagonist Esmolol Given at Reperfusion Improves Survival After Prolonged Ventricular Fibrillation
Authors: Killingsworth Cheryl R. , Wei Chih-Chang , Dell’Italia Louis J. , Ardell Jeffrey L. , Kingsley Melody A. , Smith William M. , Ideker Raymond E. , Walcott Gregory P.
Published: May 2004

Background—

High catecholamine concentrations are cytotoxic to cardiac myocytes. We hypothesized that myocardial interstitial catecholamine levels are greatly elevated immediately after long-duration ventricular fibrillation (VF), defibrillation, and reperfusion and that the short-acting β-antagonist esmolol administered at reperfusion would protect against this catecholamine surge and improve survival.

Methods and Results—

In part 1 of this study, catecholamines from myocardial interstitial fluid (ISF) and aortic and coronary sinus plasma were quantified by use of
3
H-labeled radioenzymatic assay in 8 open-chest, anesthetized pigs. Eight minutes of electrically induced VF was followed by internal defibrillation and reperfusion. By 4 minutes of VF, ISF norepinephrine increased significantly, from 1.3±0.3 to 7.4±2.4 ng/mL. Epinephrine increased significantly, from 0.4±0.2 to 1.5±0.7 ng/mL. ISF norepinephrine and epinephrine peaked at 219.2±92.1 and 63.7±25.1 ng/mL after defibrillation and reperfusion and decreased significantly to 12.2±3.5 and 6.7±3.1 ng/mL 23 minutes after defibrillation. Transcardiac catecholamine changes were similar. In part 2, 8 minutes of VF was followed by external defibrillation in anesthetized, closed-chest pigs. Animals received 1.0 mg/kg esmolol (n=8) or saline (n=8) intravenously at the start of cardiopulmonary resuscitation (CPR). Advanced cardiac life support, including CPR and epinephrine, was delivered to both groups. Esmolol before reperfusion improved return of spontaneous circulation and 4-hour survival (7/8 versus 3/8 survivors, χ
2
P
<0.05).

Conclusions—

Transcardiac and ISF norepinephrine and epinephrine levels are briefly massively elevated after 8 minutes of VF, defibrillation, and reperfusion. A short-acting β-antagonist administered immediately after defibrillation improves return of spontaneous circulation and 4-hour survival after this prolonged VF.
Prostaglandin E
2
Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP
4
Authors: Xiao Chun-Yang , Yuhki Koh-ichi , Hara Akiyoshi , Fujino Takayuki , Kuriyama Shuhko , Yamada Takehiro , Takayama Koji , Takahata Osamu , Karibe Hideji , Taniguchi Takanobu , Narumiya Shuh , Ushikubi Fumitaka
Published: May 2004

Background—

In the heart with acute myocardial infarction, production of prostaglandin (PG) E
2
increases significantly. In addition, several subtypes of PGE
2
receptors (EPs) have been reported to be expressed in the heart. The role of PGE
2
in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE
2
via EP
4
, an EP subtype, in I/R injury using mice lacking EP
4
(EP
4
−/−
mice).

Methods and Results—

In murine cardiac ventricle, competitive reverse transcription–polymerase chain reaction revealed the highest expression level of EP
4
mRNA among EP mRNAs. EP
4
−/−
mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP
4
−/−
hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP
4
agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP
4
agonist, was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. Notably, a similar cardioprotective effect was observed even when it was administered 50 minutes after coronary occlusion.

Conclusions—

Both endogenous PGE
2
and an exogenous EP
4
agonist protect the heart from I/R injury via EP
4
. The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.
Six- and Twelve-Month Results From First Human Experience Using Everolimus-Eluting Stents With Bioabsorbable Polymer
Authors: Grube Eberhard , Sonoda Shinjo , Ikeno Fumiaki , Honda Yasuhiro , Kar Saibal , Chan Charles , Gerckens Ulrich , Lansky Alexandra J. , Fitzgerald Peter J.
Published: May 2004

Background—

Everolimus, an active immunosuppressive and antiproliferative agent of the same family as sirolimus (rapamycin), has demonstrated significant reduction of neointimal proliferation in animal studies. The First Use To Underscore restenosis Reduction with Everolimus (FUTURE) I trial was the first in-human experience to evaluate the safety and efficacy of everolimus-eluting stents (EES), coated with a bioabsorbable polymer, compared with bare metal stents (BMS).

Methods and Results—

FUTURE I was a prospective, single-blind, randomized trial that enrolled 42 patients with de novo coronary lesions (EES 27, BMS 15). Patient and lesion characteristics were comparable between the groups. Major adverse cardiac event rates were low at 30 days and 6 months, without any early or late stent thrombosis for either group (
P
=NS). Between 6 and 12 months, there were no additional reports of major adverse cardiac events. The 6-month angiographic in-stent restenosis rate was 0% versus 9.1% (1 patient) (
P
=NS), with an associated late loss of 0.11 mm versus 0.85 mm (
P
<0.001), and the in-segment restenosis rate was 4% (1 patient) and 9.1% (1 patient) (
P
=NS) for EES and BMS, respectively. Intravascular ultrasound analysis revealed a significant reduction of percent neointimal volume in EES compared with BMS (2.9±1.9 mm
3
/mm versus 22.4±9.4 mm
3
/mm,
P
<0.001). There was no late stent malapposition in either group. The safety and efficacy of the EES appeared to be sustained at 12 months.

Conclusions—

In this initial clinical experience, EES with bioabsorbable polymer demonstrated a safe and efficacious method to reduce in-stent neointimal hyperplasia and restenosis.
Impact of Sirolimus-Eluting Stents on Outcome in Diabetic Patients
Authors: Moussa Issam , Leon Martin B. , Baim Donald S. , O’Neill William W. , Popma Jeffery J. , Buchbinder Maurice , Midwall Jay , Simonton Charles A. , Keim Emily , Wang Patrick , Kuntz Richard E. , Moses Jeffrey W.
Published: May 2004

Background—

Randomized clinical trials have shown that a sirolimus-eluting stent significantly reduces restenosis after percutaneous coronary revascularization. Diabetic patients are known to have a higher risk of restenosis compared with nondiabetic patients. The purpose of this analysis was to determine the impact of sirolimus-eluting stents on outcomes of diabetic compared with nondiabetic patients.

Methods and Results—

The SIRIUS (SIRolImUS-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions) trial is a randomized, double-blind study that compared sirolimus-eluting and bare metal stent implantation in 1058 patients with de novo native coronary artery lesions. Diabetes mellitus was present in 279 (26%) patients (diabetes mellitus group, 131 patients received sirolimus-eluting stents and 148 patients received bare metal stents) and was absent in 778 patients (no–diabetes mellitus group, 402 patients received sirolimus-eluting stents and 376 patients received bare metal stents). At 270 days, target lesion revascularization was reduced in diabetic patients from 22.3% with bare metal stents to 6.9% with sirolimus-eluting stents (
P
<0.001) and in nondiabetic patients from 14.1% to 2.99% (
P
<0.001), respectively. Major adverse cardiac events were reduced in diabetic patients from 25% with bare metal stents to 9.2% with sirolimus-eluting stents (
P
<0.001) and from 16.5% to 6.5% (
P
<0.001) in nondiabetic patients, respectively.

Conclusions—

Implantation of sirolimus-eluting stents compared with bare metal stents in de novo coronary lesions reduces major adverse cardiac events in patients with and without diabetes mellitus. However, among patients receiving sirolimus-eluting stents, there remains a trend toward a higher frequency of repeat intervention in diabetic patients compared with nondiabetic patients, particularly in the insulin-requiring patients.
HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis
Authors: Merx Marc W. , Liehn Elisa A. , Janssens Uwe , Lütticken Rudolf , Schrader Jürgen , Hanrath Peter , Weber Christian
Published: May 2004

Background—

HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis.

Methods and Results—

Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24±0.09 to 0.87±0.11 mL · min
−1
· g
−1
in untreated mice (
P
<0.005; n=12), while remaining unaltered (1.21±0.08 mL · min
−1
· g
−1
at baseline and 1.15±0.1 mL · min
−1
· g
−1
20 hours after CLP,
P
=NS, n=12) in CLP mice treated with simvastatin]. Untreated CLP mice remained refractory to β-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin. Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis. In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium.

Conclusions—

Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.
Stimulation of Cyclic GMP Production via AT
2
and B
2
Receptors in the Pressure-Overloaded Aorta After Banding
Authors: Hiyoshi Hiromi , Yayama Katsutoshi , Takano Masaoki , Okamoto Hiroshi
Published: May 2004

Abdominal aortic banding induces upregulation of the angiotensin II (Ang II) type-2 (AT
2
) receptor, thereby decreasing the contractile response to Ang II in the thoracic aorta of the rat. The aim of this study was to use a mouse model to clarify the mechanisms by which the banding elicits upregulation of the aortic AT
2
receptor and the subsequent attenuation of Ang II responsiveness. Concomitantly with the elevation in blood pressure and plasma renin concentration after banding, AT
2
-receptor mRNA levels in the thoracic aorta rapidly increased in mice within 4 days. Upregulation of the AT
2
receptor, as well as blood pressure elevation after banding, was abolished by losartan administration. The contractile response to Ang II was depressed in aortic rings of banding mice but not of sham mice, and was restored by either the AT
2
-receptor antagonist PD123319 or the bradykinin B
2
-receptor antagonist icatibant. cGMP content in the thoracic aorta of banding mice was 9-fold greater than that of sham mice, and the elevation was reduced to sham levels 1 hour after intravenous injection of PD123319 or icatibant. When aortic rings were incubated with Ang II, cGMP content increased in banding rings but not in sham rings; the pretreatment with PD123319 or icatibant inhibited Ang II-induced cGMP production. These results suggest that aortic banding induces upregulation of the AT
2
receptor through increased circulating Ang II via the AT
1
receptor, thereby activating a vasodilatory pathway in vessels through the AT
2
receptor via the kinin/cGMP system.
Differences in Left Ventricular Structure Between Black and White Hypertensive Adults
Authors: Kizer Jorge R. , Arnett Donna K. , Bella Jonathan N. , Paranicas Mary , Rao D.C. , Province Michael A. , Oberman Albert , Kitzman Dalane W. , Hopkins Paul N. , Liu Jennifer E. , Devereux Richard B.
Published: May 2004

The degree to which ethnic differences in left ventricular structure among hypertensive adults are independent of clinical and hemodynamic factors remains uncertain. We assessed whether left ventricular mass and geometry differ between black and white hypertensives after accounting for differences in such factors. Our study group comprised 1060 black and 580 white hypertensive participants free of valvular or coronary disease in a population-based cohort. Blood pressure was measured during a clinic visit and echocardiography was performed using standardized protocols. After controlling for clinical and hemodynamic parameters (cardiac index, peripheral resistance index, and pulse pressure/stroke index), both left ventricular mass and relative wall thickness were higher in blacks than whites (173.9±30.9 versus 168.3±24.3 grams,
P
=0.006, and 0.355±0.055 versus 0.340±0.055 grams,
P
<0.001). Similarly, the adjusted risk of having left ventricular hypertrophy, whether indexed by height
2.7
or by body surface area, was greater for blacks than for whites (odds ratio: 1.80; 95% CI: 1.29 to 2.51; and odds ratio: 2.50; 95% CI: 1.58 to 3.96, respectively), and this was also true for concentric geometry (odds ratio: 2.28; 95% CI: 1.22 to 4.25). Further adjustment for relatedness in this genetic epidemiological study did not attenuate these differences. Our findings confirm the strong association between black ethnicity and increased left ventricular mass and relative wall thickness in hypertensive adults and demonstrate that these differences are independent of standard clinical and hemodynamic parameters. Whether such differences relate to distinct ambulatory pressure profiles or an ethnic propensity to cardiac hypertrophy requires further investigation.
Enhanced Contractility of Renal Afferent Arterioles From Angiotensin-Infused Rabbits
Authors: Wang Dan , Chabrashvili Tina , Wilcox Christopher S.
Published: May 2004

We tested the hypothesis that cyclooxygenase (COX), thromboxane A
2
synthase (TxA
2
-S), thromboxane prostanoid receptors (TP-Rs), or superoxide anion (O
2
−
) mediates enhanced contractions of renal afferent arterioles (Aff) of angiotensin II (Ang II)-infused rabbits. Rabbits were infused with vehicle (sham), Ang II 60 ng·kg
−1
·min
−1
(Ang II 60) or 200 ng·kg
−1
·min
−1
(Ang II 200). There was a selective enhanced vasoconstriction of Affs from Ang II 60 rabbits to Ang II (Δdiameter−78±8% versus −43±9%;
P
<0.01) that was normalized by a TP-R antagonist but not by a superoxide dismutase (SOD) mimetic. Affs from Ang II 200 rabbits had increased (
P
<0.01) mRNA for COX-2 and enhanced vasoconstriction to Ang II, U-46 619 (TP-R mimetic), and endothelin-1 that was normalized by ifetroban plus tempol together. Endothelium removal enhanced Ang II responses of Affs from sham rabbits but blunted responses from Ang II 200 rabbits and abolished responses to ifetroban. Affs from Ang II 200 rabbits had an endothelium-dependent contraction factor (EDCF) response to that was blunted (
P
<0.001) by a SOD mimetic or antagonists of COX-1 or TxA
2
-S but normalized by antagonists of COX-2 or TP-R. Thus, enhanced Ang II responses in Affs from rabbits infused with slow pressor Ang II are mediated independently by O
2
−
in the vascular smooth muscle cells and by an EDCF that is principally a vasoconstrictor prostaglandin generated by COX-2 >−1 activating TP-Rs, whereas enhanced responses in rabbits infused with a lower Ang II dose are dependent on TP-R but not O
2
−
.
Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1
Authors: Verheule Sander , Sato Toshiaki , Everett Thomas , Engle Steven K. , Otten Dan , Rubart-von der Lohe Michael , Nakajima Hisako O. , Nakajima Hidehiro , Field Loren J. , Olgin Jeffrey E.
Published: May 2004

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys
33
ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (
P
<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.
Endothelin-1–Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac Myocytes
Authors: Kawamura Teruhisa , Ono Koh , Morimoto Tatsuya , Akao Masaharu , Iwai-Kanai Eri , Wada Hiromichi , Sowa Naoya , Kita Toru , Hasegawa Koji
Published: May 2004

Endothelin-1 (ET-1) is a potent survival factor that protects cardiac myocytes from apoptosis. ET-1 induces cardiac gene transcription and protein expression of antiapoptotic B cell leukemia-2 (bcl-2) in a calcineurin-dependent manner. A cellular target of adenovirus early region 1A (E1A) oncoprotein, p300 also activates
bcl-2
transcription in cardiac myocytes and is required for their survival. p300 acts as a calcineurin-regulated nuclear factors of activated T lymphocytes (NFATc), downstream targets of calcineurin. In addition, the bcl-2 promoter contains multiple NFAT consensus sequences. These findings prompted us to investigate the role of NFATc in ET-1–dependent and p300-dependent
bcl-2
transcription in cardiac myocytes. In primary cardiac myocytes prepared from neonatal rats, mutation of 2 NFAT sites within the bcl-2 promoter completely abolished the ET-1– and p300-induced increases in the activity of this promoter. We show here that p300 markedly potentiates the binding of NFATc1 to the bcl-2 NFAT element by interacting with NFATc1 in an E1A-dependent manner. On the other hand, stimulation of cardiac myocytes with ET-1 causes nuclear translocation of NFATc1, which interacts with p300 and increases DNA binding. Expression of E1A did not change the cardiac nuclear localization of NFATc1 but blocked its interaction with p300, DNA binding, and bcl-2 promoter activation. These findings suggest that ET-1–dependent NFATc signaling associates with p300 in the transactivation of
bcl-2
gene in cardiac myocytes.
Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease
Authors: Christiansen Jesse , Dyck John D. , Elyas Basil G. , Lilley Margaret , Bamforth J. Stephen , Hicks Mark , Sprysak Kathleen A. , Tomaszewski Robert , Haase Shelagh M. , Vicen-Wyhony Leanne M. , Somerville Martin J.
Published: May 2004

Congenital heart disease (CHD), comprising structural or functional abnormalities present at birth, is the most common birth defect in humans. Reduced expression of connexin40 (Cx40) has been found in association with atrial fibrillation, and deletion of Cx40 in a mouse model causes various structural heart abnormalities in 18% of heterozygotes. We screened 505 unrelated CHD cases for deletions or duplications of the Cx40 gene (
GJA5
) by real-time quantitative PCR, in order to determine whether altered copy number of this gene may be associated with a cardiac phenotype in humans. Dosage of Cx40 flanking genes (
ACPL1
and Cx50 gene,
GJA8
) was determined by real-time PCR for all apparent positive cases. In total, 3 cases were found to carry deletions on chromosome 1q21.1 spanning
ACPL1
, Cx40, and Cx50 genes. Absence of heterozygosity was observed in all 3 index cases over a 1.5- to 3-Mb region. Samples from the parents of two cases were obtained, and microsatellites across 1q21.1 were genotyped. One of the apparently unaffected parents was found to carry this deletion. All 3 index cases presented with obstruction of the aortic arch as the common structural cardiac malformation, and had no consistent dysmorphic features. Genotyping of 520 unrelated normal controls for this deletion was negative. We hypothesize that this 1q21.1 multigene deletion is associated with a range of cardiac defects, with anomalies of the aortic arch being a particular feature.
Proangiogenic Action of Thyroid Hormone Is Fibroblast Growth Factor–Dependent and Is Initiated at the Cell Surface
Authors: Davis Faith B. , Mousa Shaker A. , O’Connor Laura , Mohamed Seema , Lin Hung-Yun , Cao H. James , Davis Paul J.
Published: May 2004

The effects of thyroid hormone analogues on modulation of angiogenesis have been studied in the chick chorioallantoic membrane model. Generation of new blood vessels from existing vessels was increased 3-fold by either
l
-thyroxine (T
4
; 10
−7
mol/L) or 3,5,3′-triiodo-
l
-thyronine (10
−9
mol/L). T
4
–agarose reproduced the effects of T
4
, and tetraiodothyroacetic acid (tetrac) inhibited the effects of both T
4
and T
4
–agarose. Tetrac itself was inactive and is known to block actions of T
4
on signal transduction that are initiated at the plasma membrane. T
4
and basic fibroblast growth factor (FGF2) were comparably effective as inducers of angiogenesis. Low concentrations of FGF2 combined with submaximal concentrations of T
4
produced an additive angiogenic response. Anti-FGF2 inhibited the angiogenic effect of T
4
. The proangiogenic effects of T
4
and FGF2 were blocked by PD 98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor. Endothelial cells (ECV304) treated with T
4
or FGF2 for 15 minutes demonstrated activation of MAPK, an effect inhibited by PD 98059 and the protein kinase C inhibitor CGP41251. Reverse transcription–polymerase chain reaction of RNA extracted from endothelial cells treated with T
4
revealed increased abundance of
FGF2
transcript at 6 to 48 hours, and after 72 hours, the medium of treated cells showed increased FGF2 content, an effect inhibited by PD 98059. Thus, thyroid hormone is shown to be a proangiogenic factor. This action, initiated at the plasma membrane, is MAPK dependent and mediated by FGF2.
Ubiquitin-Proteasome System and Proteasome Inhibition: New Strategies in Stroke Therapy
Authors: Wojcik Cezary , Di Napoli Mario
Published: May 2004

Background and Purpose—

Proteasomes are large multicatalytic proteinase complexes that are found in the cytosol and in the nucleus of eukaryotic cells with a central role in cellular protein turnover. The ubiquitin-proteasome system (UPS) has a central role in the selective degradation of intracellular proteins. Among the key proteins whose levels are modulated by the proteasome are those involved in the control of inflammatory processes, cell cycle regulation, and gene expression. There are now overwhelming data suggesting that the UPS contributes to cerebral ischemic injury.

Summary of Review—

Proteasome inhibition is a potential treatment option for stroke. Thus far, proof of principle has been obtained from studies in several animal models of cerebral ischemia. Treatment with proteasome inhibitors reduces effectively neuronal and astrocytic degeneration, cortical infarct volume, infarct neutrophil infiltration, and NF-κB immunoreactivity with an extension of the neuroprotective effect at least 6 hours after ischemic insult. However, it is clear that the UPS represents a central pathway for the processing and metabolism of multiple proteins with critical roles in cellular function. To avoid eliciting significant side effects associated with complete inhibition of the proteasome and the possible immunosuppressive effects from persistent suppression of NF-κB activation, it is critical that we understand how to partially and temporally attenuate proteasome function to elicit the desired therapeutic effect before any large-scale use in humans.

Conclusion—

This review highlights the most recent advances in our knowledge on UPS, as well as the early experience of using proteasome inhibition strategies to treat acute stroke.
Health Care Resource Use After Acute Stroke in the Glycine Antagonist in Neuroprotection (GAIN) Americas Trial
Authors: Rundek Tanja , Nielsen Kirsten , Phillips Stephen , Johnston Karen C. , Hux Marg , Watson David
Published: May 2004

Background and Purpose—

To compare 3-month stroke outcomes and stroke-related health care resource use between the US and Canada in the Glycine Antagonist in Neuroprotection (GAIN) Americas study. Delivery of medical care for stroke patients, often driven by efforts to curb costs, varies substantially between countries. Data on the potential impact of these variations on clinical outcomes are sparse.

Methods—

The analysis of health care resource included total length of stay (LOS) in hospital, intensive care unit (ICU), and acute-care ward or rehabilitation unit, or both; number of outpatient rehabilitation sessions and visits to a physician; place of residence after discharge; and employment status. Cox proportional hazards models and logistic regression were used to calculate survival hazards and predictors of favorable functional outcome (Barthel Index of 95 to 100).

Results—

One thousand six hundred four patients who were independent before stroke (mean age: 69.9±12.7 years, 53% men, 85% ischemic stroke, 69% in the US) were included. Three-month survival and functional outcome did not differ between the US and Canada. Survival rate was 80% in both countries. Favorable functional outcome was achieved in 43% of Canadian and 47% of US patients. Fewer Canadian patients received treatment in ICU (19% versus 63% in the US), and Canadians had longer stays in hospital or rehabilitation facility (median: 33 days versus 16 days in the US).

Conclusion—

Despite similar 3-month survival and functional outcome, patterns of health care resource varied substantially between the US and Canada. US patients had more intensive early care; Canadian patients had longer hospitalizations and rehabilitation care. Further research is required to determine the most cost-effective treatment and rehabilitation plan for people who have a stroke.
Aortic Arch Atherosclerotic Lesions and the Recurrence of Ischemic Stroke
Authors: Fujimoto Shigeru , Yasaka Masahiro , Otsubo Ryoichi , Oe Hiroshi , Nagatsuka Kazuyuki , Minematsu Kazuo
Published: May 2004

Background and Purpose—

Aortic arch atherosclerotic lesions are often associated with embolic brain infarction. We investigated the relationship between stroke recurrence and the characteristics of aortic arch atherosclerotic lesions.

Methods—

Among 487 stroke patients who underwent transesophageal echocardiography, 283 patients with brain embolism diagnosed without significant occlusive lesions (≥50%) in their cerebral arteries were included in this study. We measured the intima-media thickness (IMT) and evaluated the extension and mobility of the aortic arch atherosclerotic lesions. During a mean follow-up period of 3.4 years, we investigated the relationship between stroke recurrence and the various characteristics of the aortic arch atherosclerotic lesions.

Results—

An IMT ≥4.0 mm was found in 67 patients (25.3%). In 51 of these patients, the aortic lesions extended to the origin of the branches of the arch. Recurrences of cerebral ischemic events were found in 32 patients (recurrence group) and not in the other 251 (nonrecurrence group). Aortic atheroma ≥4.0 mm (41% versus 22%), aortic atheroma extending to the branches (63% versus 39%), and both (38% versus 16%) were more frequently seen in the recurrence group than in the nonrecurrence group (
P
<0.05,
P
<0.1,
P
<0.01, respectively). After adjustment for age and the presence of hypertension, an aortic atheroma that was ≥4.0 mm as well as extending to the branches was found to be an independent predictor of ischemic stroke recurrence (hazard ratio=2.42,
P
<0.05).

Conclusions—

Stroke recurrence is associated with the severity of the atheroma (IMT ≥4.0 mm) and plaque extension to the branches.
Cerebral Blood Flow and Metabolism During Infusion of Norepinephrine and Propofol in Patients With Bacterial Meningitis
Authors: Møller Kirsten , Qvist Tavs , Tofteng Flemming , Sahl Christian , Sønderkær Signe , Dethloff Thomas , Knudsen Gitte Moos , Larsen Fin Stolze
Published: May 2004

Background and Purpose—

In patients with severe bacterial meningitis, norepinephrine is often infused to increase mean arterial pressure (MAP). This increases cerebral blood flow (CBF), but it is unknown if this increase is caused by impaired cerebral autoregulation or by a cerebral effect of norepinephrine through increased cerebral metabolism. The latter possibility implies a CBF–metabolism coupling. This has not been studied during meningitis. We studied the effect of norepinephrine and propofol on CBF and oxidative metabolism in patients with severe bacterial meningitis.

Methods—

In seven patients with pneumococcal meningitis and 7 healthy subjects, norepinephrine was infused intravenously; patients also underwent intravenous propofol infusion. Global CBF was measured by the Kety–Schmidt technique; cerebral oxidative metabolism and net flux of norepinephrine and epinephrine were calculated from measured arterial-to-jugular venous concentration differences (a-vD).

Results—

During norepinephrine infusion, MAP increased from a median value of 79 (range, 70 to 89) to 99 (98 to 129) mm Hg in patients, and from 87 (72 to 103) to 123 (112 to 132) mm Hg in controls. CBF increased in patients (51 [48 to 60] to 59 [54 to 77] mL/100 g per minute) but remained unchanged in controls. The cerebral metabolic rate of oxygen (CMRO
2
) decreased in patients and remained unchanged in controls. No cerebral net flux of norepinephrine or epinephrine was found at any time in the 2 groups. During propofol infusion, CMRO
2
, and the a-vDO
2
decreased whereas CBF was unchanged.

Conclusions—

In patients with severe bacterial meningitis, norepinephrine increases both MAP and CBF but not CMRO
2
, indicating impaired autoregulation. Propofol reduces CBF relatively less than cerebral metabolism, suggesting a resetting of the CBF–CMRO
2
relationship.