bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockade of the Renin-Angiotensin System Increases Plasma Adiponectin Levels in Type-2 Diabetic Patients with Proteinuria
Authors: Yenicesu Müjdat , Yilmaz Mahmut Ilker , Caglar Kayser , Sonmez Alper , Eyileten Tayfun , Acikel Cengizhan , Kilic Selim , Bingol Necati , Bingol Sezin , Vural Abdulgaffar
Published: February 2005

Background/Aims: Adiponectin seems to be an important modulator for metabolic and vascular diseases. A case study was designed to measure plasma adiponectin levels and to investigate the effects of angiotensin-converting enzyme inhibitors on adiponectin levels in type-2 diabetic patients with proteinuria. Methods: Forty-nine patients (28 males, 21 females) and 23 healthy volunteers (13 males, 10 females) were included in the case study. Patients with proteinuria were treated with 5 mg/day ramipril (n = 21) for 4 weeks. Results: Adiponectin levels of patients were significantly lower than those of healthy volunteers (p < 0.001). There were significant negative correlations between adiponectin concentrations and insulin levels as well as the homeostasis model assessment (HOMA) index in the patient group (r = –0.655, p < 0.001; r = –0.469, p = 0.001, respectively). There was also a significant negative correlation between plasma adiponectin concentrations and the degree of proteinuria (r = –0.912, p < 0.001). Plasma adiponectin levels in patients with proteinuria (n = 21; 4.81 ± 3.17 µg/ml) were significantly lower than those without proteinuria (n = 28; 10.25 ± 2.03 µg/ml; p < 0.001). After the treatment period, adiponectin levels significantly increased (p < 0.001) and proteinuria, plasma insulin, and HOMA indexes significantly decreased in the treatment group (p < 0.001, p < 0.001, p = 0.002, respectively). Conclusions: The results suggest that adiponectin is inversely correlated with proteinuria and treatment with ramipril both corrects proteinuria and increases the low adiponectin levels in diabetic patients.
Biocompatibility Parameters of Different Dialysis Membranes Assessed during Systemic Inflammation
Authors: Gueler F. , Gwinner W. , Schiborr C. , Martin M. , Klos A. , Kirsch T. , Fiebeler A. , Haller H. , Fliser D.
Published: February 2005

Background: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. Methods: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 ± 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. Results: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 ± 783 to 5,423 ± 761 ng/ml; PA: from 7,379 ± 980 to 5,690 ± 714 ng/ml; VEC: from 7.377 ± 714 to 5,360 ± 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-α, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 ± 41 to 477 ± 41 ng/ml; PA: from 437 ± 42 to 449 ± 40 ng/ml; VEC: from 461 ± 43 to 460 ± 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. Conclusion: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.
Plasma Levels of Adrenomedullin in Patients with Adrenoleukodystrophy/Adrenomyeloneuropathy
Authors: Letizia C. , D’Erasmo E. , Subioli S. , Di Biase A. , Benedetti S. , Bizzarri C. , Ubertini G. , Cappa M.
Published: February 2005

Background/Aims: Adrenomedullin (AM) is a recently purified hypotensive peptide and its encoding gene has been sequenced from a human pheochromocytoma. High levels of AM have been shown in Addison’s disease (AD). X-linked adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) is a peculiar adrenal insufficiency due to an accumulation of very-long chain fatty acid in adrenal cells and it is very often associated with a devastating demyelination of the central nervous system. Methods: We studied the AM plasma levels of 22 patients with ALD/AMN (18 with hypoadrenalism, ALDa, and 4 with normal adrenal function, ALDb) and compared them with 18 males with classical AD and 16 normal male subjects. All patients with hyposurrenalism were studied before treatment with hydrocortisone. Results: Both patients with ALD/AMN and AD showed increased levels of AM and all of them showed a significant difference from the control group (p < 0.0001). The plasma renin activity was higher in all patient groups than in the control group (p <0.001 ALDa, ALDb and AD vs. control group). The aldosterone levels were higher in ALDa and ALDb groups than AD (ALDa vs. AD p < 0.01; ALDb vs. control group p < 0.05; AD vs. controls p < 0.01). ACTH plasma levels were higher in ALDa and AD than ALDb and the control group (ALDa vs. AD not significant while ALDa and AD vs. control p <0.0001). Conclusions: Our data indicate that plasma AM levels in ALDa, ALDb and AD are higher than controls. These results were previously described in untreated AD. While classical AD patients show complete adrenal insufficiency (both mineralocorticoid and glucocorticoid defects), ALD/AMN patients show a less compromised glomerular function, indicating that AM is not completely correlated with mineralocorticoid insufficiency, and that the exact mechanism responsible for the increased AM levels in ALD/AMN is still unknown.
Redox Modulation of Vascular Tone
Authors: Gutterman David D. , Miura Hiroto , Liu Yanping
Published: February 2005

Opening of potassium channels on vascular smooth muscle cells with resultant hyperpolarization plays a central role in several mechanisms of vasodilation. For example, in the arteriolar circulation where tissue perfusion is regulated, there is an endothelial derived hyperpolarizing factor that opens vascular smooth muscle calcium-activated potassium channels, eliciting dilation. Metabolic vasodilation involves the opening of sarcolemmal ATP-sensitive potassium channels. Adrenergic dilation as well as basal vasomotor tone in several vascular beds depend upon voltage-dependent potassium channels in smooth muscle. Thus hyperpolarization through potassium channel opening is a fundamental mechanism for vasodilation. Disease states such as coronary atherosclerosis and its risk factors are associated with elevated levels of reactive oxygen (ROS) and nitrogen species that have well-defined inhibitory effects on nitric oxide–mediated vasodilation. Effects of ROS on hyperpolarization mechanisms of dilation involving opening of potassium channels are less well understood but are very important because hyperpolarization-mediated dilation often compensates for loss of other dilator mechanisms. We review the effect of ROS on potassium channel function in the vasculature. Depending on the oxidative species, ROS can activate, inhibit, or leave unaltered potassium channel function in blood vessels. Therefore, discerning the activity of enzymes regulating production or degradation of ROS is important when assessing tissue perfusion in health and disease.
Endothelium-Derived Hydrogen Peroxide Accounts for the Enhancing Effect of an Angiotensin-Converting Enzyme Inhibitor on Endothelium-Derived Hyperpolarizing Factor–Mediated Responses in Mice
Authors: Fujiki Takako , Shimokawa Hiroaki , Morikawa Keiko , Kubota Hiroshi , Hatanaka Makoto , Talukder M.A. Hassan , Matoba Tetsuya , Takeshita Akira , Sunagawa Kenji
Published: February 2005

Background—

We have recently identified that endothelium-derived hydrogen peroxide (H
2
O
2
) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H
2
O
2
accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved.

Methods and Results—

Control and eNOS
−/−
mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H
2
O
2
, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K
Ca
channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS
−/−
mice (n=6).

Conclusions—

These results indicate that endothelium-derived H
2
O
2
accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H
2
O
2
theory.
Tissue-Engineered Blood Vessels
Authors: Hoenig Michel R. , Campbell Gordon R. , Rolfe Barbara E. , Campbell Julie H.
Published: February 2005

Although vascular bypass grafting remains the mainstay for revascularization for ischemic heart disease and peripheral vascular disease, many patients do not have healthy vessels suitable for harvest. Thus, prosthetic grafts made of synthetic polymers were developed, but their use is limited to high-flow/low-resistance conditions because of poor elasticity, low compliance, and thrombogenicity of their synthetic surfaces. To fill this need, several laboratories have produced in vivo or in vitro tissue-engineered blood vessels using molds or prosthetic or biodegradable scaffolds, but each artificial graft has significant problems. Recently, conduits have been grown in the peritoneal cavity of the same animals in which they will be grafted, ensuring no rejection, in the short time of 2 to 3 weeks. Remodeling occurs after grafting such that the tissue is almost indistinguishable from native vessels. This conduit is derived from cells of bone marrow origin, opening new possibilities in vascular modeling and remodeling.
Stable 5,6-Epoxyeicosatrienoic Acid Analog Relaxes Coronary Arteries Through Potassium Channel Activation
Authors: Yang Wenqi , Gauthier Kathryn M. , Reddy L. Manmohan , Sangras Bhavani , Sharma Kamalesh K. , Nithipatikom Kasem , Falck John R. , Campbell William B.
Published: February 2005

5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxation. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 μmol/L) induced concentration-dependent relaxations, with maximal relaxation of 86±5% and EC
50
of 1 μmol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 μmol/L; max relaxation 43±9%); the ATP-sensitive K
+
channel inhibitor glybenclamide (10 μmol/L; max relaxation 49±6%); and the large conductance calcium-activated K
+
channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38±6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K
+
to 20 mmol/L. Whole-cell outward K
+
current was increased nearly 6-fold by PTPA (10 μmol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy)pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46±13% and 52±7%, respectively; EC
50
1μmol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether–containing prostaglandins that activate ATP-sensitive K
+
channels and (2) activation of smooth muscle large conductance calcium-activated K
+
channels. PDPAs only activate large conductance calcium-activated K
+
channels.
Soluble Epoxide Hydrolase Is a Main Effector of Angiotensin II–Induced Hypertension
Authors: Jung Oliver , Brandes Ralf P. , Kim In-Hae , Schweda Frank , Schmidt Ronald , Hammock Bruce D. , Busse Rudi , Fleming Ingrid
Published: February 2005

The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II–induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 μg/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II–induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II–induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 μmol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II–pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II–treated mice, AUDA was without effect. The ω-hydroxylase inhibitor
N-
methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II–treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II–induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice.
Interaction of Angiotensin II Type 1 and D
5
Dopamine Receptors in Renal Proximal Tubule Cells
Authors: Zeng Chunyu , Yang Zhiwei , Wang Zheng , Jones John , Wang Xiaoyan , Altea Joanna , Mangrum Amy J. , Hopfer Ulrich , Sibley David R. , Eisner Gilbert M. , Felder Robin A. , Jose Pedro A.
Published: February 2005

Angiotensin II type 1 (AT
1
) receptor and D
1
and D
3
dopamine receptors directly interact in renal proximal tubule (RPT) cells from normotensive Wistar-Kyoto rats (WKY). There is indirect evidence for a D
5
and AT
1
receptor interaction in WKY and spontaneously hypertensive rats (SHR). Therefore, we sought direct evidence of an interaction between AT
1
and D
5
receptors in RPT cells. D
5
and AT
1
receptors colocalized in WKY cells. Angiotensin II decreased D
5
receptors in WKY cells in a time- and concentration-dependent manner (EC
50
=2.7×10
−9
M; t
1/2
=4.9 hours), effects that were blocked by an AT
1
receptor antagonist (losartan). In SHR, angiotensin II (10
−8
M/24 hours) also decreased D
5
receptors (0.96±0.08 versus 0.72±0.08; n=12) and to the same degree as in WKY cells (1.44±0.07 versus 0.92±0.08). However, basal D
5
receptors were decreased in SHR RPT cells (SHR 0.96±0.08; WKY 1.44±0.07; n=12 per strain;
P
<0.05) and renal brush border membranes of SHR compared with WKY (SHR 0.54±0.16 versus WKY 1.46±0.10; n=5 per strain;
P
<0.05). Angiotensin II decreased AT
1
receptor expression in WKY (1.00±0.04 versus 0.72±0.08; n=8;
P
<0.05) but increased it in SHR (0.96±0.04 versus 1.32±0.08; n=8;
P
<0.05). AT
1
and D
5
receptors also interacted in vivo; renal D
5
receptor protein was higher in mice lacking the AT
1A
receptor (AT
1A
−/−; 1.61±0.31; n=6) than in wild-type littermates used as controls (AT
1A
+/+; 0.81±0.08; n=6;
P
<0.05), and renal cortical AT
1
receptor protein was higher in D
5
receptor null mice than in wild-type littermates (1.18±0.08 versus 0.84±0.07; n=4;
P
<0.05). We conclude that D
5
and AT
1
receptors interact with each other. Altered interactions between AT
1
and dopamine receptors may play a role in the pathogenesis of hypertension.
Matrix Protein–Specific Regulation of Cx43 Expression in Cardiac Myocytes Subjected to Mechanical Load
Authors: Shanker Amit J. , Yamada Kiyomi , Green Karen G. , Yamada Kathryn A. , Saffitz Jeffrey E.
Published: February 2005

To elucidate mechanisms responsible for mechanotransduction in the heart and define the effects of remodeling of the extracellular matrix, we cultured neonatal rat ventricular myocytes on native type I collagen, fibronectin, or denatured collagen and subjected them to uniaxial, pulsatile stretch. Changes in expression of the cardiac gap junction protein, Cx43, were measured by confocal microscopy and immunoblotting. Cells grown on fibronectin or denatured collagen exhibited significantly greater Cx43 expression than cells grown on native collagen. Stretch induced a ≈2-fold increase in Cx43 expression in cells grown on native collagen but no increase in cells grown on fibronectin or denatured collagen. Incubation of cells on native collagen with a peptide containing the arginine-glycine-aspartate (RGD) motif upregulated Cx43 expression equivalent to that induced by stretch. Nonselective activation of integrin signaling with MnCl
2
also upregulated Cx43 expression in cells grown on native collagen. This effect was blocked completely by pretreatment with anti-β
1
integrin antibody but not by anti-β
3
integrin antibody. Stretch led to a marked increase in β
1
integrin immunofluorescent signal in cells grown on native collagen but not in cells grown on fibronectin or denatured collagen. Stretch-induced upregulation of Cx43 was also blocked by anti-β
1
integrin antibody. Thus, matrix protein-myocyte interactions regulate Cx43 expression via β
1
integrin signaling initiated by mechanical stimulation in cells grown on native type I collagen, or by RGD-integrin signaling independent of mechanical stress in cells grown on fibronectin or denatured collagen. Changes in the composition of the extracellular matrix may affect electrical coupling in cardiac myocytes.
Coronary Artery and Orifice Development Is Associated With Proper Timing of Epicardial Outgrowth and Correlated Fas Ligand Associated Apoptosis Patterns
Authors: Eralp Ismail , Lie-Venema Heleen , DeRuiter Marco C. , van den Akker Nynke M.S , Bogers Ad J.J.C. , Mentink Monica M.T. , Poelmann Robert E. , Gittenberger-de Groot Adriana C.
Published: February 2005

The proepicardial organ provides differentiated cell types to the myocardial wall and facilitates coronary development. Ingrowth of the coronary arteries into the aorta has recently been linked to apoptosis. This study was set up to examine the effect of an inhibition of epicardial outgrowth on apoptotic patterning and coronary development. Epicardial outgrowth was blocked at HH15–17 in quail embryos, which survived until HH25–35 (n=33). Embryos with complete inhibition of outgrowth did not survive after HH29. These embryos presented with thin compact myocardium, devoid of vessels. In embryos with delayed epicardial outgrowth the phenotype was less severe, and surviving embryos were studied up to HH35. In these embryos, myocardial vascularization was poor and apoptosis in the peritruncal region at HH30 was diminished. Embryos at HH35 displayed an abnormal coronary network and absent coronary orifices. In a further set of experiments (n=10), outgrowth was inhibited in chicken embryos at HH15, followed by transplantation of a quail proepicardial organ into the pericardial cavity to rescue cardiac phenotype. These chimeras were studied at HH29 and HH35. Myocardial development was restored; however, in 3 of 4 embryos (HH35), the coronary orifices were absent. Examination of double stainings of quail-chicken chimeras revealed that EPDCs produce Fas ligand as an apoptotic inductor at sites of coronary ingrowth. In the absence of proper timing of epicardial outgrowth, myocardial development and vascularization are disturbed. Also apoptosis in the peritruncal region is diminished. During later development, this leads to defective or absent connections of the coronary system to the systemic circulation.
Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca
2+
Release
Authors: Harris David M. , Mills Geoffrey D. , Chen Xiongwen , Kubo Hajime , Berretta Remus M. , Votaw V. Scott , Santana Luis F. , Houser Steven R.
Published: February 2005

Depressed contractility of failing myocytes involves a decreased rate of rise of the Ca
2+
transient. Synchronization of Ca
2+
release from the junctional sarcoplasmic reticulum (SR) is responsible for the rapid rise of the normal Ca
2+
transient. This study examined the idea that spatially and temporally dyssynchronous SR Ca
2+
release slows the rise of the cytosolic Ca
2+
transient in failing feline myocytes. Left ventricular hypertrophy (LVH) with and without heart failure (HF) was induced in felines by constricting the ascending aorta. Ca
2+
transients were measured in ventricular myocytes using confocal line scan imaging. Ca
2+
transients were induced by field stimulation, square wave voltage steps, or action potential (AP) voltage clamp. SR Ca
2+
release was significantly less well spatially and temporally synchronized in field-stimulated HF versus control or LVH myocytes. Surprisingly, depolarization of HF cells to potentials where Ca
2+
currents (
I
Ca
) were maximal resynchronized SR Ca
2+
release. Correspondingly, decreases in the amplitude of
I
Ca
desynchronized SR Ca
2+
release in control, LVH, and HF myocytes to the same extent. HF myocytes had significant loss of phase 1 AP repolarization and smaller
I
Ca
density, which should both reduce Ca
2+
influx. When normal myocytes were voltage clamped with HF AP profiles SR Ca
2+
release was desynchronized. SR Ca
2+
release becomes dyssynchronized in failing feline ventricular myocytes because of reductions in Ca
2+
influx induced in part by alterations in early repolarization of the AP. Therefore, therapies that restore normal early repolarization should improve the contractility of the failing heart.
Hyperthermia Masks the Neuroprotective Effects of Tissue Plaminogen Activator
Authors: Noor Raza , Wang Chen Xu , Shuaib Ashfaq
Published: February 2005

Background and Purpose—

Previously, we have shown that hyperthermia significantly increased neuronal damage after ischemic injury in a focal embolic model of stroke in rats. In the present study, we examined the effects of hyperthermia on the efficacy of thrombolytic therapy in this stroke model.

Methods—

In part A, efficacy of tissue plaminogen activator (tPA) treatment was examined in normothermic and hyperthermic rats after embolization of preformed clots into middle cerebral artery (MCA). In part B, brain perfusion deficits were assessed in rats after MCA occlusion. In part C, blood–brain barrier (BBB) permeability was examined in rats after MCA occlusion. In part D, we examined the influence of hyperthermia on fibrinolytic activity of tPA in vitro.

Results—

Results showed that treatment with tPA significantly reduced infarct volume in normothermic and 38°C hyperthermic rats. When compared with normothermic rats, perfusion deficits in hyperthermic rats were significantly increased at both 3 hours and 6 hours after ischemic injury. Compared with normothermic sham-operated rats, Evans blue dye extravasation was increased in the injured rats with 39°C hyperthermia. In vitro study showed that hyperthermia increased the fibrinolytic activity of tPA.

Conclusions—

The present study shows that hyperthermia masks the neuroprotective effects of tPA treatment after ischemic injury and that this may be caused by increased BBB permeability, increased edema, and early progression of ischemic penumbral region to irreversibly damaged tissue as shown by progressively increasing perfusion deficits in hyperthermic rats.
Clinical Predictors of Transient Ischemic Attack, Stroke, or Death Within 30 Days of Carotid Angioplasty and Stenting
Authors: Kastrup Andreas , Gröschel Klaus , Schulz Jörg B. , Nägele Thomas , Ernemann Ulrike
Published: February 2005

Background and Purpose—

Carotid angioplasty and stenting (CAS) is currently being assessed in the treatment of severe carotid stenosis. However, little data are available concerning patient-related factors affecting the risk of CAS. The purpose of this study was to identify potential clinical risk factors for the development of postprocedural deficits after CAS.

Methods—

The clinical characteristics of 299 patients (217 men, 82 women; mean age 69±9 years) who underwent CAS for asymptomatic (n=129, 43%) or symptomatic (n=170, 57%) stenoses and the combined 30-day complication rates (any transient ischemic attack [TIA], minor stroke, major stroke, or death) were analyzed with logistic regression analysis.

Results—

The overall 30-day TIA rate was 3.7%; the minor stroke rate was 5.3%, the major stroke rate was 0.7%, and the death rate was 0.7%. Although patients presenting with a hemispherical TIA or minor stroke had a significantly higher risk than asymptomatic patients (odds ratio [OR] 5.69; 95% confidence interval [CI], 2.03 to 19.57;
P
<0.001), the complication rates between patients presenting with a retinal TIA and asymptomatic patients was comparable (OR, 1.42; 95% CI, 0.13 to 9.09;
P
=0.6). Multivariate regression analysis revealed advanced age (OR, 1.06; 95% CI, 1 to 1.11;
P
<0.05), stroke (OR, 8; 95% CI, 2.6 to 24.4;
P
<0.01) or hemispherical TIA (OR, 4.7; 95% CI, 1.6 to 13.3) as presenting symptoms as independent clinical predictors of the combined 30-day outcome measures any TIA, stroke, or death.

Conclusion—

Aside from advanced age and symptom status, the type of presenting event predicts postprocedural complications after CAS. When evaluating the outcome of CAS and comparing this treatment modality to surgery, patients should be stratified according to their presenting event.
Stratified Gray-Scale Median Analysis and Color Mapping of the Carotid Plaque
Authors: Sztajzel R. , Momjian S. , Momjian-Mayor I. , Murith N. , Djebaili K. , Boissard G. , Comelli M. , Pizolatto G.
Published: February 2005

Background and Purpose—

To determine whether a stratified gray-scale median (GSM) analysis of the carotid plaque combined with color mapping could predict plaque histology better than an overall GSM measurement.

Methods—

Thirty-one carotid plaques derived from 28 patients undergoing carotid endarterectomy were investigated by ultrasound. GSMs of the whole plaque were used as measurement of echogenicity. A profile of the regional GSM as a function of distance from the plaque surface could be generated. Plaque pixels were further mapped into 3 different colors depending on their GSM value.

Results—

Plaques with large calcifications presented the highest GSM values, and those with large hemorrhagic areas or with a predominant necrotic core exhibited the lowest. Fibrous plaques had intermediate GSM values. A necrotic core located in a juxtalumenal position was associated with significantly lower GSM values (
P
=0.009) and with a predominant red color (GSM <50) at the surface (
P
=0.0019). With respect to the thickness of the fibrous cap and the position of the necrotic core, the sensitivity and specificity of the predominant red color of the whole plaque was respectively 45% and 67% and 53% and 75%; considering the predominant red color of the surface, the sensitivity and specificity increased to 73% and 67% and 84% and 75%, respectively.

Conclusions—

The stratified GSM measurement combined with color mapping showed a good correlation with the different histopathological components and further allowed identification with good accuracy of determinants of plaque instability. This approach should be investigated in a prospective, natural history study.
Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease
Authors: Othman Maha , Notley Colleen , Lavender Frances Louise , White Helen , Byrne Christopher D. , Lillicrap David , O'Shaughnessy Denise Frances
Published: February 2005

Interaction between the platelet glycoprotein Ibα (GPIbα) receptor and its adhesive ligand von Willebrand factor (VWF) has a critical role in the process of hemostasis. Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder that results from gain-of-function mutations in the GPIBA gene. We studied this gene from 5 members of a previously unreported family with a PT-VWD phenotype. We identified a novel in-frame deletion of 27 base pair (bp) in the macroglycopeptide region. This deletion was not found in the unaffected family members or in 50 healthy controls. The patients' platelets expressed normal quantities of GPIb/IX/V complex on their surface and the mutant (Mut) GPIbα was expressed at levels indistinguishable from the wild-type (WT) receptor on the surface of transfected Chinese hamster ovary (CHO) β/IX cells. Analysis of ristocetin-mediated 125I-VWF binding showed that the Mut receptor binds VWF in the absence of ristocetin and displays an increased sensitivity to lower concentrations of the modulator. This is the first report of a gain-of-function mutation in the GPIbα receptor outside the VWF-binding domain in patients with PT-VWD. The mutation provides a molecular basis for the PT-VWD phenotype and supports a role for the macroglycopeptide region in receptor function.
Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo
Authors: Hamasaki Makoto , Hideshima Teru , Tassone Pierfrancesco , Neri Paola , Ishitsuka Kenji , Yasui Hiroshi , Shiraishi Norihiko , Raje Noopur , Kumar Shaji , Picker Donald H. , Jacob Gary S. , Richardson Paul G. , Munshi Nikhil C. , Anderson Kenneth C.
Published: February 2005

Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorκBα (IκBα) and nuclear factor κB (NFκB) p65 phosphorylation triggered by tumor necrosis factor α (TNF-α). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM.
Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients
Authors: Aukrust Pål , Luna Luisa , Ueland Thor , Johansen Rune F. , Müller Fredrik , Frøland Stig S. , Seeberg Erling C. , Bjørås Magnar
Published: February 2005

Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4+ and CD8+ T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4+ T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8+ T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4+ T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4+ T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4+ T cells in patients with HIV infection. (Blood. 2005; 105:4730-4735)
Correlation of exhaled breath temperature with bronchial blood flow in asthma
Authors: Paredi Paolo , Kharitonov Sergei A , Barnes Peter J
Published: February 2005

In asthma elevated rates of exhaled breath temperature changes (Δe°T) and bronchial blood flow (Qaw) may be due to increased vascularity of the airway mucosa as a result of inflammation.

We investigated the relationship of Δe°T with Qaw and airway inflammation as assessed by exhaled nitric oxide (NO). We also studied the anti-inflammatory and vasoactive effects of inhaled corticosteroid and β2-agonist.

Δe°T was confirmed to be elevated (7.27 ± 0.6 Δ°C/s) in 19 asthmatic subjects (mean age ± SEM, 40 ± 6 yr; 6 male, FEV1 74 ± 6 % predicted) compared to 16 normal volunteers (4.23 ± 0.41 Δ°C/s, p < 0.01) (30 ± 2 yr) and was significantly increased after salbutamol inhalation in normal subjects (7.8 ± 0.6 Δ°C/ s, p < 0.05) but not in asthmatic patients. Qaw, measured using an acetylene dilution method was also elevated in patients with asthma compared to normal subjects (49.47 ± 2.06 and 31.56 ± 1.6 μl/ml/min p < 0.01) and correlated with exhaled NO (r = 0.57, p < 0.05) and Δe°T (r = 0.525, p < 0.05). In asthma patients, Qaw was reduced 30 minutes after the inhalation of budesonide 400 μg (21.0 ± 2.3 μl/ml/min, p < 0.05) but was not affected by salbutamol.

Δe°T correlates with Qaw and exhaled NO in asthmatic patients and therefore may reflect airway inflammation, as confirmed by the rapid response to steroids.
Associations between diet and disease activity in ulcerative colitis patients using a novel method of data analysis
Authors: Magee Elizabeth A , Edmond Laurie M , Tasker Shiona M , Kong San Choon , Curno Richard , Cummings John H
Published: February 2005

Background

The relapsing nature and varying geographical prevalence of ulcerative colitis (UC) implicates environmental factors such as diet in its aetiology.

Methods

In order to determine which foods might be related to disease activity in UC a new method of dietary analysis was developed and applied. Eighty-one UC patients were recruited at all stages of the disease process. Following completion of a 7 d diet diary, clinical assessment including a sigmoidoscopic examination (scale 0 (normal mucosa) to 6 (very active disease)) was conducted. Food weights for each person were adjusted (divided) by the person's calorific intake for the week. Each food consumed was given a food sigmoidoscopy score (FSS) calculated by summing the products of the (adjusted) weight of food consumed and sigmoidoscopy score for each patient and occurrence of food and dividing by the total (adjusted) weight of the food consumed by all 81 patients. Thus, foods eaten in large quantities by patients with very active disease have high FSSs and vice versa. Foods consumed by <10 people or weighing <1 kg for the whole group were excluded, leaving 75 foods.

Results

High FSS foods were characterized by high levels of the anti-thiamin additive sulfite (Mann-Whitney, p < 0.001), i.e. bitter, white wine, burgers, soft drinks from concentrates, sausages, lager and red wine. Caffeine also has anti-thiamin properties and decaffeinated coffee was associated with a better clinical state than the caffeine containing version. Beneficial foods (average intake per week) included pork (210 g), breakfast cereals (200 g), lettuce (110 g), apples and pears (390 g), milk (1250 ml), melon (350 g), bananas (350 g), bacon (120 g), beef and beef products (500 g), tomatoes (240 g), soup (700 g), citrus fruits (300 g), fish (290 g), yogurt (410 g), cheese (110 g), potatoes (710 g) and legumes (120 g).

Conclusions

The dietary analysis method described provides a new tool for establishing relationships between diet and disease and indicates a potentially therapeutic diet for UC.
Long-term survival from gastrocolic fistula secondary to adenocarcinoma of the transverse colon
Authors: Forshaw Matthew J , Dastur Jamasp K , Murali Kothandaraman , Parker Michael C
Published: February 2005

Background

Gastrocolic fistula is a rare presentation of both benign and malignant diseases of the gastrointestinal tract. Malignant gastrocolic fistula is most commonly associated with adenocarcinoma of the transverse colon in the Western World. Despite radical approaches to treatment, long-term survival is rarely documented.

Case presentation

We report a case of a 24-year-old woman who presented with the classic triad of symptoms associated with gastrocolic fistula. Radical en-bloc surgery and adjuvant chemotherapy were performed. She is still alive ten years after treatment.

Conclusions

Gastrocolic fistula is an uncommon presentation of adenocarcinoma of the transverse colon. Radical en-bloc surgery with adjuvant chemotherapy may occasionally produce long-term survival.
LDL receptor expression on T lymphocytes in old patients with Down syndrome
Authors: Corsi Massimiliano M , Malavazos Alexis E , Passoni Daniele , Licastro Federico
Published: February 2005

Background

In Down syndrome patients several metabolic abnormalities have been reported, some involving the lipid metabolism. The level of LDL in plasma is the major determinant of the risk of vascular disease. There appear to be no studies on the LDL receptor in Down syndrome patients.

Methods

Flow cytometric methods for measuring the LDL receptor in peripheral blood mononuclear cells (PBMC) can identify patients with hypercholesterolemia. We applied this method in 19 old patients with Down syndrome and 23 healthy controls.

Results

Down syndrome patients had high levels of triglycerides and low levels of HDL, and high levels of CRP. We also found a down-regulation of LDL receptor expression.

Conclusions

Down syndrome patients show no increase in the frequency of cardiovascular disease. The low incidence in cardiovascular disease despite the low level of HDL, high levels of CRP and reduction of LDL receptor expression lead to the conclusion that either these are not risk factors in these patients or that other risks factors – not yet identified – are considerably lower.
Reference gene selection for quantitative real-time PCR analysis in virus infected cells: SARS corona virus, Yellow fever virus, Human Herpesvirus-6, Camelpox virus and Cytomegalovirus infections
Authors: Radonić Aleksandar , Thulke Stefanie , Bae Hi-Gung , Müller Marcel A , Siegert Wolfgang , Nitsche Andreas
Published: February 2005

Ten potential reference genes were compared for their use in experiments investigating cellular mRNA expression of virus infected cells. Human cell lines were infected with Cytomegalovirus, Human Herpesvirus-6, Camelpox virus, SARS coronavirus or Yellow fever virus. The expression levels of these genes and the viral replication were determined by real-time PCR. Genes were ranked by the BestKeeper tool, the GeNorm tool and by criteria we reported previously. Ranking lists of the genes tested were tool dependent. However, over all, β-actin is an unsuitable as reference gene, whereas TATA-Box binding protein and peptidyl-prolyl-isomerase A are stable reference genes for expression studies in virus infected cells.
GAD‐Reactive T Cells Were Mainly Detected in Autoimmune‐Related Type 1 Diabetic Patients with HLA DR9
Authors: ITOH ARATA , SHIMADA AKIRA , KODAMA KEIICHI , MORIMOTO JIRO , SUZUKI RYUJI , OIKAWA YOICHI , IRIE JUNICHIRO , NAKAGAWA YOSHINORI , SHIGIHARA TOSHIKATSU , KANAZAWA YASUHIKO , OKUBO YOSHIAKI , MOTOHASHI YOSHIKO , MARUYAMA TARO , SARUTA TAKAO
Published: February 2005

Abstract: Type 1 diabetes mellitus (T1DM) is considered to be a T cell‐mediated disease, and many reports suggest that some HLA types, especially HLA DR4 and DR9, convey susceptibility to T1DM in Japanese. We investigated the association between T cell reactivity against GAD and HLA types in “islet‐associated autoantibody‐positive” T1DM in Japanese. Blood samples were obtained from 36 “autoantibody‐positive” type 1 diabetic patients with HLA DR4 or DR9 and 23 type 2 diabetic patients with HLA DR4 or DR9 as controls. They were divided into three groups, DR4/9, DR4/X, and DR9/X groups. In each HLA type group, GAD‐reactive IFN‐γ‐producing CD4+ cells were assessed by means of intracellular cytokine staining for flow cytometry. Type 1 diabetic patients with HLA DR9/X had significantly higher numbers of GAD‐reactive IFN‐γ‐producing CD4+ cells as compared to type 1 diabetic patients with DR4/X or DR4/9 (P < 0.05) and all type 2 diabetic patients. There was no significant difference in the number of GAD‐reactive IFN‐γ‐producing CD4+ cells between type 1 diabetic and type 2 diabetic patients belonging to the DR4/X and DR4/9 groups. There was an association between T cell reactivity against GAD and HLA DR9 in Japanese type 1 diabetes.
Monocytic Expression Behavior of Cytokines in Diabetic Patients upon Inflammatory Stimulation
Authors: GIULIETTI ANNAPAULA , STOFFELS KATINKA , DECALLONNE BRIGITTE , OVERBERGH LUT , MATHIEU CHANTAL
Published: February 2005

Abstract: Cytokines are involved in the pathogenesis of type 1 diabetes. The disease is characterized by T cell‐mediated β cell destruction and a biased Th1 cytokine pattern. Type 2 diabetes also presents an inflammatory cytokine imbalance. In this study, mRNA expression of cytokines IL‐12, TNF‐α, IL‐1, and IL‐6 was studied in monocytes from diabetic patients after in vitro immune stimulation. Whereas IL‐12p40 was highly expressed in type 1 diabetic patients, TNF‐α, IL‐1, and IL‐6 transcripts were elevated in type 1 but especially type 2 diabetic patients compared with healthy controls, suggesting an important proinflammatory milieu. We conclude that circulating monocytes from type 1 as well as type 2 diabetic patients have an aberrant cytokine profile when stimulated by an immune stimulus such as IFNγ. This condition not only is likely to be involved in disease pathogenesis, but may contribute to its later complications.
Randomized Trial of Two Intravenous Schedules of the Topoisomerase I Inhibitor Liposomal Lurtotecan in Women With Relapsed Epithelial Ovarian Cancer: A Trial of the National Cancer Institute of Canada Clinical Trials Group
Authors: Dark Graham G. , Calvert A. Hilary , Grimshaw Robert , Poole Christopher , Swenerton Ken , Kaye Stan , Coleman Robert , Jayson Gordon , Le Tien , Ellard Susan , Trudeau Marc , Vasey Paul , Hamilton Marta , Cameron Terri , Barrett Emma , Walsh Wendy , McIntosh Lynn , Eisenhauer Elizabeth A.
Published: February 2005

Purpose

Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study.

Patients and Methods

Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m2/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m2/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior.

Results

Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B.

Conclusion

The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.