bluuebunny/crossref_metadata_2025 huggingface dataset:
In Vivo Magnetic Resonance Imaging of Coronary Thrombosis Using a Fibrin-Binding Molecular Magnetic Resonance Contrast Agent
Authors: Botnar René M. , Buecker Arno , Wiethoff Andrea J. , Parsons Edward C. , Katoh Marcus , Katsimaglis George , Weisskoff Robert M. , Lauffer Randall B. , Graham Philip B. , Gunther Rolf W. , Manning Warren J. , Spuentrup Elmar
Published: July 2004

Background—

The advent of fibrin-binding molecular magnetic resonance (MR) contrast agents and advances in coronary MRI techniques offers the potential for direct imaging of coronary thrombosis. We tested the feasibility of this approach using a gadolinium (Gd)-based fibrin-binding contrast agent, EP-2104R (EPIX Medical Inc), in a swine model of coronary thrombus and in-stent thrombosis.

Methods and Results—

Ex vivo and in vivo sensitivity of coronary MR thrombus imaging was tested by use of intracoronarily delivered Gd-DTPA–labeled fibrinogen thrombi (n=6). After successful demonstration, in-stent coronary thrombosis was induced by x-ray–guided placement of thrombogenic-coated, MR-lucent stents (n=5). After stent placement, 60 μmol of EP-2104R was injected via the left main coronary artery. Free-breathing, navigator-gated 3D coronary MR angiography and thrombus imaging were performed (1) before and after stent placement and (2) before and after EP-2104R. Thrombi were confirmed by x-ray angiography and autopsy. Fibrinogen thrombi: 5 of 6 intracoronarily delivered Gd-labeled fibrinogen clots (≈250 μmol/L Gd) were visible on MRI and subsequently confirmed by x-ray angiography. In-stent thrombi: in-stent thrombosis was observed in all stents after EP-2104R. Four of 5 thrombi were confirmed by x-ray angiography. Chemical analysis of 2 thrombi demonstrated 99 to 147 μmol/L Gd.

Conclusions—

We demonstrate the feasibility of MRI of coronary thrombus and in-stent thrombosis using a novel fibrin-binding molecular MR contrast agent. Potential applications include detection of coronary in-stent thrombosis or thrombus burden in patients with acute coronary syndromes.
Carotid Artery Plaque Burden, Stiffness, and Mortality Risk in Elderly Men
Authors: Störk Stefan , van den Beld Annewieke W. , von Schacky Clemens , Angermann Christiane E. , Lamberts Steven W.J. , Grobbee Diederick E. , Bots Michiel L.
Published: July 2004

Background—

Indicators of carotid atherosclerosis may confer additional prognostic value and guide clinicians in cardiovascular risk assessment. Carotid artery morphology (plaque burden) and function (stiffness indexes) as predictors of all-cause and cardiovascular mortality were prospectively evaluated in elderly men.

Methods and Results—

Cardiovascular risk profile was measured in 367 independently living men (mean± SD age, 78±4 years). The number of carotid plaques was assessed by B-mode ultrasound, and arterial stiffness was quantified with a wall tracker system. During 48 months of follow-up, 70 deaths (28 cardiovascular) occurred. The total number of carotid plaques was the parameter most closely related to prognosis. In the age-adjusted multivariate Cox model, all-cause mortality was predicted by number of plaques (hazard ratio [HR] per 1-unit increase, 1.35; 95% confidence interval [CI], 1.12 to 1.64). Predictors of cardiovascular mortality in the respective model were number of plaques (HR, 1.18; 95% CI, 1.04 to 1.33) and Young’s elastic modulus (HR, 1.68; 95% CI, 1.26 to 2.26). Number of plaques improved the prognostic utility in any prognosis model when added to commonly available cardiovascular risk information. In contrast, stiffness indexes offered no consistent additive value.

Conclusions—

In elderly men, carotid artery plaque burden is a strong independent predictor of all-cause and cardiovascular mortality in the years to come. The additional value of carotid artery stiffness measurements as a pathophysiologically related entity appears to be limited in this age group and, if anything, confined to cardiovascular mortality risk.
Regression of Coronary Atherosclerosis by Simvastatin
Authors: Jensen Lisette Okkels , Thayssen Per , Pedersen Knud Erik , Stender Steen , Haghfelt Torben
Published: July 2004

Background—

Angiography of the coronary arteries reflects only changes in luminal dimensions. With intravascular ultrasound, cross-sectional images can be obtained and area measurements can be added to calculate volumes of the external elastic membrane (EEM), plaque plus media (P+M), and lumen. The aim of this study was to investigate the effect of lipid lowering by simvastatin on coronary atherosclerotic P+M as changes in volumes of EEM, P+M, and lumen.

Methods and Results—

In 40 male patients with hypercholesterolemia, ischemic heart disease, and a nonsignificant coronary artery lesion in a not previously revascularized coronary artery, serial intravascular ultrasound studies with an ECG-triggered pullback were performed at baseline, after 3 months on a lipid-lowering diet, and after another 12 months on simvastatin 40 mg/d. Mean length of the analyzed atherosclerotic segments was 5.9±3.3 mm. After 12 months on simvastatin, a significant reduction in P+M volume of 6.3% (
P
=0.002) was observed, whereas only a nonsignificant reduction in EEM volume of 1.8% was seen without any concomitant change in lumen volume. A significant reduction in total cholesterol of 31.0% (6.1±0.8 versus 4.2±0.7 mmol/L,
P
<0.001) and LDL cholesterol of 42.6% (4.0±0.8 versus 2.2±0.6 mmol/L,
P
<0.001) was obtained.

Conclusions—

Lipid-lowering therapy with simvastatin for 12 months is associated with a significant P+M regression in coronary arteries measured as reduction in P+M and EEM volumes without any concomitant change in lumen volume.
Improvement of Postnatal Neovascularization by Human Adipose Tissue-Derived Stem Cells
Authors: Miranville A. , Heeschen C. , Sengenès C. , Curat C.A. , Busse R. , Bouloumié A.
Published: July 2004

Background—

Several studies have suggested that stem cells are present in the stroma-vascular fraction (SVF) of adipose tissue (AT).

Methods and Results—

To characterize the cell populations that compose the SVF of human AT originating from subcutaneous and visceral depots, fluorescence-activated cell sorter analysis was performed by use of fluorescent antibodies directed against the endothelial and stem cell markers CD31, CD34, CD133, and ABCG2. The freshly harvested SVF contained large numbers of CD34
+
cells as well as cells expressing CD133 and ABCG2. Further analysis of the CD34
+
cells revealed 2 CD34
+
cell populations with differential expression of the endothelial cell marker CD31. Selection of the CD34
+
/CD31
−
cells by use of magnetic microbeads, followed by cell culture, demonstrated that this cell population could differentiate under appropriate conditions into endothelial cells. Moreover, in mouse ischemic hindlimb, intravenous injection of CD34
+
/CD31
−
cells was associated with an increase in the blood flow and the capillary density and an incorporation of the cells in the leg vasculature.

Conclusions—

Our data indicate the presence of a cell population within the SVF of human AT characterized as CD34
+
/CD31
−
exhibiting characteristics of endothelial progenitor cells. Therefore, human AT might represent a source of stem/progenitor cells useful for cell therapy to improve vasculogenesis in adults.
Celecoxib, a Cyclooxygenase-2 Inhibitor, Reduces Neointimal Hyperplasia Through Inhibition of Akt Signaling
Authors: Yang Han-Mo , Kim Hyo-Soo , Park Kyung-Woo , You Hyun-Jeong , Jeon Soo-In , Youn Seock-Won , Kim Sung-Hwan , Oh Byung-Hee , Lee Myoung-Mook , Park Young-Bae , Walsh Kenneth
Published: July 2004

Background—

Celecoxib has been shown to have antitumor effects that may be mediated through the cyclooxygenase-independent inhibition of Akt signaling. Here, we examined the effects of celecoxib on neointimal formation after balloon injury and its mechanism of action.

Methods and Results—

In vitro experiments were performed to evaluate the effects of celecoxib on the Akt/GSK signaling axis and the viability of rat vascular smooth muscle cells (VSMCs). In vivo experiments examined the effects of celecoxib, aspirin, and vehicle on neointimal growth after denudation injury to rat carotid arteries. In vitro, celecoxib suppressed the phosphorylation of Akt and GSK in cultured VSMCs, leading to a reduction in viable cell number, which was reversed by transduction of constitutively active Akt. Such a reduction in cell number was mediated by inhibition of proliferation and induction of apoptosis. In vivo, celecoxib reduced injury-induced phosphorylation of Akt and GSK, reduced VSMC proliferation, and increased caspase-3 activation and VSMC apoptosis at 3 days after injury, whereas aspirin had no effect. At 2 weeks after injury, celecoxib reduced intima-to-media ratio, whereas aspirin had no effect. Adenovirus-mediated delivery of dominant negative Akt was as effective as celecoxib at inhibiting neointimal formation. Conversely, gene delivery of constitutively active Akt significantly reversed the inhibition of intimal hyperplasia by celecoxib, providing causal evidence that the modulation of Akt signaling by celecoxib is a physiologically relevant mechanism.

Conclusions—

Celecoxib is a potential inhibitor of neointimal formation by blocking injury-induced Akt activation. These findings suggest a potential use for celecoxib in the prevention of restenosis after angioplasty.
Implantation of Immature Neonatal Cardiac Cells Into the Wall of the Aorta in Rats
Authors: Dai Wangde , Hale Sharon L. , Kloner Robert A.
Published: July 2004

Background—

Morphological and functional development of implanted neonatal cardiac cells in the wall of the abdominal aorta in rats was investigated.

Methods and Results—

Cardiomyocytes from neonatal Fischer rats (both sexes) or medium were injected into the wall of the abdominal aorta in female Fischer rats (n=22 in each group). Two or 6 weeks later, the grafted site was exposed and fixed for histological and immunohistological examination. Polymerase chain reaction analysis of the
SRY
gene to identify male cells was performed in the treated aortas. Seven of 10 cell-treated aortas but none of 10 medium-treated aortas showed spontaneous rhythmic beating at the grafted site after excision of the heart at 2 weeks. Polymerase chain reaction of the
SRY
gene was positive in 3 cell-treated aortas and none of 3 medium-treated aortas at 6 weeks. Hematoxylin-and-eosin staining showed viable grafts in 9 of 10 aortas at 2 weeks and 9 of 9 aortas at 6 weeks in the cell-treated group but in none of the aortas receiving medium. Neonatal cardiomyocytes in the graft formed compact, longitudinally oriented cardiac muscle bundles and had cross-striations and vascularization. Immunohistochemical staining for sarcomeric actin was positive in 4 of 10 aortas at 2 weeks and 9 of 9 aortas at 6 weeks in the cell group but in none of the aortas in the medium group.

Conclusions—

Grafted neonatal cardiomyocytes survive, differentiate, grow, develop a blood supply, and spontaneously contract within the wall of the aorta in rats.
Aggregated Low-Density Lipoprotein Uptake Induces Membrane Tissue Factor Procoagulant Activity and Microparticle Release in Human Vascular Smooth Muscle Cells
Authors: Llorente-Cortés Vicenta , Otero-Viñas Marta , Camino-López Sandra , Llampayas Oriol , Badimon Lina
Published: July 2004

Background—

Tissue factor (TF) is the main initiator of the arterial blood coagulation system, and aggregated LDL (agLDL) are found in the arterial intima. Our hypothesis is that agLDL internalization by vascular smooth muscle cells (VSMCs) may trigger TF-procoagulant activity.

Methods and Results—

Cultured human VSMCs were obtained from human coronary arteries of explanted hearts during transplant operations. VSMCs were incubated with native LDL (nLDL) or agLDL. TF mRNA was analyzed by real-time polymerase chain reaction, and cellular and released TF protein antigen were analyzed by Western blot. TF microparticle (MP) content was analyzed by flow cytometry and TF activity by a factor Xa generation test. Both nLDL and agLDL strongly and equally increased TF mRNA and cell membrane protein expression, by approximately 5- and 9-fold, respectively. A sustained TF procoagulant activity was induced by agLDL but not by nLDL (agLDL 2.46±0.22 versus nLDL 0.72±0.12 mU/mg protein at 12 hours). AgLDL increased TF antigen release (agLDL 5.64±0.4 versus nLDL 3.28±0.22 AU) and TF MP release (agLDL 89.85±8.51 versus nLDL 19.69±4.59 TF MP/10
3
cells). TF activation and release induced by agLDL is not related to apoptosis. Blockade of LDL receptor-related protein, a receptor for agLDL, prevented the agLDL-induced release of TF protein and TF MP.

Conclusions—

VSMC-TF expression is upregulated by both nLDL and agLDL. However, only agLDL engagement to LDL receptor-related protein induced cellular TF procoagulant activity and TF release by human VSMCs.
Serum Total and Lipoprotein Cholesterol Levels and Awareness, Treatment, and Control of Hypercholesterolemia in China
Authors: He Jiang , Gu Dongfeng , Reynolds Kristi , Wu Xigui , Muntner Paul , Zhao Jiangong , Chen Jing , Liu Donghai , Mo Jingping , Whelton Paul K.
Published: July 2004

Background—

Cardiovascular disease has become the leading cause of death in China. We examined the levels of serum total and lipoprotein cholesterol and status of awareness, treatment, and control of hypercholesterolemia in China.

Methods and Results—

A cross-sectional survey in a nationally representative sample of 15 540 Chinese adults 35 to 74 years of age was conducted during 2000 to 2001. Serum cholesterol was measured by use of standard methods, and information on treatment of hyperlipidemia was obtained by use of a standard questionnaire. Age-standardized mean levels of total, HDL, and LDL cholesterol and triglycerides were 186.1, 51.7, 109.5, and 128.1 mg/dL, respectively. Of the Chinese population 35 to 74 years of age, 23.8% (112 500 000 persons) had borderline high total cholesterol (200 to 239 mg/dL), and 9.0% (42 540 000 persons) had high total cholesterol (≥240 mg/dL). The population estimates for borderline high (130 to 159 mg/dL), high (160 to 189 mg/dL), and very high (≥190 mg/dL) LDL cholesterol were 17.0% (80 122 000 persons), 5.1% (24 329 000 persons), and 2.7% (12 822 000 persons), respectively. In addition, 19.2%, or 90 803 000 persons, had a low HDL cholesterol (<40 mg/dL). Among those who had a total cholesterol ≥200 mg/dL or who were on cholesterol-lowering medications, the proportion of men and women who were aware, treated, and controlled was only 8.8% and 7.5%, 3.5% and 3.4%, and 1.9% and 1.5%, respectively.

Conclusions—

The prevalence of hypercholesterolemia was relatively high and the percentage of adults with controlled blood cholesterol was low in China. Prevention and treatment of hypercholesterolemia should be an important component of a national strategy to reduce the substantial and increasing burden of cardiovascular disease in China.
Genetic Variation in
CYP11B2
and
AT1R
Influences Heart Rate Variability Conditional on Sodium Excretion
Authors: Stolarz Katarzyna , Staessen Jan A. , Kawecka-Jaszcz Kalina , Brand Eva , Bianchi Giuseppe , Kuznetsova Tatiana , Tikhonoff Valérie , Thijs Lutgard , Reineke Thomas , Babeanu Speranta , Casiglia Edoardo , Fagard Robert , Filipovský Jan , Peleška Jan , Nikitin Yuri , Struijker-Boudier Harry , Grodzicki Tomasz
Published: July 2004

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (
CYP11B2
C–344T) and the type-1 angiotensin II receptor (
AT1R
A1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype–genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype–genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number of
CYP11B2
–344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of the
AT1R
1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with the
CYP11B2
and
AT1R
polymorphisms were nonsignificant or in the opposite direction, respectively. Thus,
CYP11B2
C–344T and
AT1R
A1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.
Safety Evaluation of Clinical Gene Therapy Using Hepatocyte Growth Factor to Treat Peripheral Arterial Disease
Authors: Morishita Ryuichi , Aoki Motokuni , Hashiya Naotaka , Makino Hirofumi , Yamasaki Keita , Azuma Junya , Sawa Yoshiki , Matsuda Hikaru , Kaneda Yasufumi , Ogihara Toshio
Published: July 2004

Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment for patients with critical limb ischemia (CLI). Because hepatocyte growth factor (HGF) has potent angiogenic activity, we investigated the safety and efficiency of HGF plasmid DNA in patients with CLI as a prospective open-labeled clinical trial. Intramuscular injection of naked HGF plasmid DNA was performed in ischemic limbs of 6 CLI patients with arteriosclerosis obliterans (n=3) or Buerger disease (n=3) graded as Fontaine III or IV. The primary end points were safety and improvement of ischemic symptoms at 12 weeks after transfection. Severe complications and adverse effects caused by gene transfer were not detected in any patients. Of particular importance, no apparent edema was observed in any patient throughout the trial. In addition, serum HGF concentration was not changed throughout the therapy period in all patients. In contrast, a reduction of pain scale of more than 1 cm in visual analog pain scale was observed in 5 of 6 patients. Increase in ankle pressure index more than 0.1 was observed in 5 of 5 patients. The long diameter of 8 of 11 ischemic ulcers in 4 patients was reduced >25%. Intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs. Although the present data are conducted to demonstrate the safety as phase I/early phase IIa, the initial clinical outcome with HGF gene transfer seems to indicate usefulness as sole therapy for CLI.
Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens
Authors: Tang Yucheng , Zhang Lixin , Yuan Jing , Akbulut Hakan , Maynard Jonathan , Linton Phyllis-Jean , Deisseroth Albert
Published: July 2004

Our goal in the present work was to characterize the multiple steps involved in overcoming the anergy that exists in tumor hosts to tumor-associated antigen (TAA). Our studies showed that the subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector resulted in secretion of the TAA/ecdCD40L protein for at least 10 days from infected cells. Binding of the TAA/ecdCD40L protein to dendritic cells (DCs) resulted in the induction of CCR-7 chemokine receptor expression and cytokine release. This was followed by migration of the DCs to regional lymph nodes. Tetramer staining, enzyme-linked immunospot (ELISPOT) assay, and cytotoxicity assay all showed that the Ad-sig-TAA/ecdCD40L vector increased the levels of splenic CD8+ T cells specific for the 2 TAAs (human MUC1 [hMUC1] and HPV E7) tested. Vaccination with the Ad-sighMUC1/ecdCD40L vector suppressed the growth of hMUC1 antigen-positive tumor cells in 100% of the test mice that were previously anergic to the hMUC1 antigen. These data suggest that Ad-sig-TAA-ecd/ecdCD40L vector injections may be of value in treating the many epithelial malignancies in which TAA-like hMUC1 is overexpressed. (Blood. 2004;104:2704-2713)
Reactive oxygen species limit neutrophil life span by activating death receptor signaling
Authors: Scheel-Toellner Dagmar , Wang Keqing , Craddock Rachel , Webb Paul R. , McGettrick Helen M. , Assi Lakhvir Kaur , Parkes Neal , Clough Louise E. , Gulbins Erich , Salmon Mike , Lord Janet M.
Published: July 2004

Neutrophils are abundant, short-lived leukocytes, and their death by apoptosis is central to hemostasis and the resolution of inflammation, yet the trigger for their entry into apoptosis is unknown. We show here that death receptor signaling, including CD95 death-inducing signaling complex (DISC) formation and caspase 8 activation, occurred early in neutrophil apoptosis. However, death receptor ligation was not required for apoptosis, suggesting a novel mechanism for caspase 8 activation. We detected ceramide generation and clustering of CD95 in lipid rafts early in neutrophil apoptosis, and neutrophil apoptosis and ceramide generation were both significantly inhibited in acid sphingomyelinase knockout (ASM–/–) mice compared to wild-type littermates. Further studies revealed that ceramide generation, CD95 clustering, and neutrophil apoptosis were dependent on reactive oxygen species (ROSs) and were preceded by a fall in reduced glutathione levels. We propose that accumulation of ROSs, as a consequence of altered redox status, initiates ligand-independent death receptor signaling via activation of ASM and clustering of preformed DISC components in lipid rafts and is therefore a primary factor limiting neutrophil life span.
Susceptibility of human fetal mesencyhmal stem cells to Kaposi sarcoma-associated herpesvirus
Authors: Parsons Christopher H. , Szomju Barbara , Kedes Dean H.
Published: July 2004

Recent reports link Kaposi sarcoma-associated herpesvirus (KSHV) infection of bone marrow cells to bone marrow failure and lymphoproliferative syndromes. The identity of the infected marrow cells, however, remains unclear. Other work has demonstrated that circulating mononuclear cells can harbor KSHV where its detection predicts the onset and severity of Kaposi sarcoma. In either setting, bone marrow precursors may serve as viral reservoirs. Since mesenchymal stem cells (MSCs) in human bone marrow regulate the differentiation and proliferation of adjacent hematopoietic precursors, we investigated their potential role in KSHV infection. Our results indicate that primary MSCs are susceptible to both cell-free and cell-associated KSHV in culture. Moreover, infection persisted within nearly half of the cells for up to 6 weeks. Thus, MSCs possess a clear capacity to support KSHV infection and warrant further exploration into their potential role in KSHV-related human disease. (Blood. 2004;104:2736-2738)
Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome
Authors: Barrans Sharon L. , Fenton James A. L. , Banham Alison , Owen Roger G. , Jack Andrew S.
Published: July 2004

FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that is differentially expressed in resting and activated B cells. FOXP1 expression has been demonstrated in a subset of diffuse large B-cell lymphomas (DLBCLs) and is more common in the nongerminal center (non-GC), activated B-cell type; however, its prognostic significance is uncertain. We analyzed presentation lymph nodes from 126 patients with nodal DLBCL, previously classified according to GC and BCL2 status, for FOXP1 protein expression using standard immunocytochemistry. Uniform high FOXP1 expression was demonstrated in 23 of 126 patients with DLBCL. This high level of expression was almost exclusively confined to patients who lacked the GC phenotype, who expressed MUM-1 and BCL2 in the absence of t(14; 18), and who were identified as a subgroup of patients with particularly poor outcomes in a group with already poor prognoses. The data presented suggest that high FOXP1 expression is an independent prognostic factor in DLBCL.
Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita
Authors: Knudson Matt , Kulkarni Shashikant , Ballas Zuhair K. , Bessler Monica , Goldman Frederick
Published: July 2004

Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described, in 10 members of a large 3-generation family, an autosomal-dominant form of DC (AD DC) that is due to a mutation in the gene-encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunologic consequences of TERC mutations, severe B lymphopenia and decreased immunoglobulin M (IgM) levels were noted. T cells were found to overexpress senescent markers, including CD57 and Fas receptor, and were moderately reduced in cell number. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent in third-generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis.
Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease
Authors: Rotola A , Merlotti I , Caniatti L , Caselli E , Granieri E , Tola M R , Di Luca D , Cassai E
Published: July 2004

The presence and the replicative state of human herpesvirus 6 (HHV-6) were evaluated in clinical samples from multiple sclerosis (MS) patients at the first time of MS diagnosis. HHV-6 variant B was present in peripheral blood mononuclear cells of 5/32 (15%) patients, but persisted with a latent infection. Viral sequences were present also in cerebrospinal fluid (CSF), both free in the liquid (7/32, 22%) and latent in the cellular fraction (3/32, 9%), as shown by analysis of viral transcription. In these cases, variant A was detected. HHV-6 DNA sequences present in the CSF were associated to mature viral particles. In fact, in vitro infectious assays of CSF showed the presence of replication-competent virions. These results show that about 20% of MS patients have active foci of HHV-6 variant A infection in the early stages of the disease and suggest that viral replication takes place within the central nervous system.
Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment
Authors: Romani Alfredo , Bergamaschi Roberto , Candeloro Elisa , Alfonsi Enrico , Callieco Roberto , Cosi Vittorio
Published: July 2004

Sixty relapsing-remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.
CD8 + T cells reduce in vitro interferon-g production in Theiler’s murine encephalomyelitis virus-induced demyelinating disease model
Authors: Denton Paul W , Tello Christina M , Melvold Roger W
Published: July 2004

In the Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease model for multiple sclerosis, regulatory CD8- T cells prevent demyelinating disease and reducein vivo interferon (IFN)-g production by anti-TMEV CD4- blast cells in BALB/c mice. We describe here that regulatory CD8- T cells reduce in vitro IFN-g production by lymph node cells from both TMEV and fowl gamma globulin immunized mice without affecting interleukin (IL)-4, IL-10, tumour growth factor-b or tumour necrosis factor-a production.
Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study
Authors: Stevenson V L , Ingle G T , Miller D H , Thompson A J
Published: July 2004

Magnetic resonance imaging (MRI) has become an accepted tool for monitoring therapeutic trials in relapsing-remitting and secondary progressive multiple sclerosis (MS); it is however unclear whether such MRI markers are equally applicable to primary progressive MS (PPMS). Forty-two patients with PPMS were reviewed five years after commencing a two-year MRI and clinical study. Clinical measures recorded at baseline and five years included both the Expanded Disability Status Scale and the MS functional composite. MRI data collected at baseline and two years included T1 and T2 lesion loads, the number of new brain and cord lesions, and measures of both brain and cord atrophy. The study demonstrated that both the number of new T2 lesions and rate of increase in ventricular volume over two years were modestly predictive of subsequent disease progression and therefore may be useful tools in the testing of new therapeutic agents in PPMS.
Measuring disability in multiple sclerosis: is the Community Dependency Index an improvement on the Barthel Index?
Authors: Nicholl L , Hobart J , Dunwoody L , Cramp F , Lowe-Strong A
Published: July 2004

The Community Dependency Index (CDI) was developed due to concerns that the Barthel Index (BI) was limited as a measure of physical function in community settings. However, no studies have compared the two rating scales within multiple sclerosis (MS). The aim of this study was to determine whether, in a community-based sample of people with MS, the CDI is a better measure than the BI. BI and CDI data were collected from 90 people with MS. Four measurement properties were compared: scaling assumptions (item mean scores, corrected item-total correlations), acceptability (score distributions, floor/ceiling effects), reliability (Cronbach’s alpha) and validity (concurrent, discriminant, group differences, relative validity). Both scales satisfied recommended criteria for scaling assumptions (indicating it was legitimate to report a summed score) and internal consistency reliability (alpha-0.85). The scales were highly correlated (r- 0.96), indicating they measured the same construct. Both scales demonstrated good group differences validity, but the BI was marginally superior. Notable ceiling effects (BI-CDI) were demonstrated for both scales, particularly in those less disabled. This study sample had relatively minor levels of disability, with over 70% still being independently mobile. In this sample of people with MS, the measurement properties of the BI and CDI examined were very similar, suggesting the CDI does not appear to have achieved its goal of better measurement.
Bladder and sexual function among women with multiple sclerosis
Authors: Borello-France Diane , Leng Wendy , O'Leary Margie , Xavier Macrina , Erickson Janet , Chancellor Michael B , Cannon Tracy W
Published: July 2004

Objective: Genitourinary dysfunction is common in women with multiple sclerosis (MS), yet few studies have evaluated the association between bladder and sexual dysfunction in these women. The aim of this study was to determine factors, including demographic and bladder function, associated with sexual dysfunction in a sample of women with MS. Methods: One hundred and thirty-three women with MS completed questionnaires related to overall heath status, bladder function and sexual function. Response frequencies and percentages were calculated for questionnaire responses. Multivariate logistic regression analyses were performed to determine predictors of sexual dysfunction. Results: Sixty-one per cent of the sample indicated that they had a problem with bladder control. Forty-seven per cent of respondents indicated that their neurological problems interfered with their sex life. Over 70% of the sample reported that they enjoyed, felt aroused and experienced orgasm during sexual activity. Not having a sexual partner and the indication of bothersome neurological problems were the best predictors of sexual dysfunction. Interestingly, patients bothered by their urge incontinence had higher levels of orgasm compared to women not bothered by urge incontinence. Conclusions: Although over half of the women reported voiding symptoms, most still enjoyed, felt aroused and could experience orgasm. Neurological symptoms and lacking a sexual partner emerged as the best predictors of sexual dysfunction. Urge incontinence may not be a risk factor for anorgasm. Our findings elucidate the complex nature of sexual dysfunction in women with MS.
Has your patient's multiple sclerosis lesion burden or brain atrophy actually changed?
Authors: Wei Xingchang , Guttmann Charles RG , Warfield Simon K , Eliasziw Michael , Mitchell J Ross
Published: July 2004

Changes in mean magnetic resonance imaging (MRI)-derived measurements between patient groups are often used to determine outcomes in therapeutic trials and other longitudinal studies of multiple sclerosis (MS). However, in day-to-day clinical practice the changes withinindividual patients may also be of interest. In this paper, we estimated the measurement error of an automated brain tissue quantification algorithm and determined the thresholds for statistically significant change of MRI-derived T2 lesion volume and brain atrophy in individual patients. Twenty patients with MS were scanned twice within 30 min. Brain tissue volumes were measured using the computer algorithm. Brain atrophy was estimated by calculation of brain parenchymal fraction. The threshold of change between repeated scans that represented statistically significant change beyond measurement error with 95% certainty was 0.65 mL for T2 lesion burden and 0.0056 for brain parenchymal fraction. Changes in lesion burden and brain atrophy below these thresholds can be safely (with 95% certainty) explained by measurement variability alone. These values provide clinical neurologists with a useful reference to interpret MRI-derived measures in individual patients.
An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis
Authors: Brady C M , DasGupta R , Dalton C , Wiseman O J , Berkley K J , Fowler C J
Published: July 2004

The majority of patients with multiple sclerosis (MS) develop troublesome lower urinary tract symptoms (LUTS). Anecdotal reports suggest that cannabis may alleviate LUTS, and cannabinoid receptors in the bladder and nervous system are potential pharmacological targets. In an open trial we evaluated the safety, tolerability, dose range, and efficacy of two whole-plant extracts of Cannabis sativa in patients with advanced MS and refractory LUTS. Patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg of each per spray) for eight weeks followed by THC-only (2.5 mg THC per spray) for a further eight weeks, and then into a long-term extension. Assessments included urinary frequency and volume charts, incontinence pad weights, cystometry and visual analogue scales for secondary troublesome symptoms. Twenty-one patients were recruited and data from 15 were evaluated. Urinary urgency, the number and volume of incontinence episodes, frequency and nocturia all decreased significantly following treatment (PB/0.05, Wilcoxon’s signed rank test). However, daily total voided, catheterized and urinary incontinence pad weights also decreased significantly on both extracts. Patient self-assessment of pain, spasticity and quality of sleep improved significantly (PB/0.05, Wilcoxon’s signed rank test) with pain improvement continuing up to median of 35 weeks. There were few troublesome side effects, suggesting that cannabis-based medicinal extracts are a safe and effective treatment for urinary and other problems in patients with advanced MS.
Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis
Authors: Debouverie M , Vandenberghe N , Morrissey S P , Anxionnat R , Pittion-Vouyovitch S , Vespignani H , Edan G
Published: July 2004

Introduction: In a number of controlled trials it was established that mitoxantrone has a beneficial effect on disease progression in multiple sclerosis (MS) patients with a worsening disease course. The aim of this study was to investigate the use of mitoxantrone in clinical practice, and especially to describe predictive parameters of its effectiveness under these conditions. Objectives and methods: In a retrospective, open-label mitoxantrone study we analysed 94 MS patients (49) relapsing-remitting MS (RRMS), 41) secondary progressive MS and 10) primary progressive MS) who received monthly 20 mg i.v. mitoxantrone and 1 g i.v. methylprednisolone for six months, and selected as a criterion of effectiveness the percentage of patients with an Expanded Disability Status Scale (EDSS) improvement of at least one point (confirmed after one year) after stopping the treatment. A multivariate analysis was undertaken to assess the predictive value of five parameters on mitoxantrone effectiveness: (1) total number of relapses since disease onset and before treatment, (2) number of relapses within the past 24 months before treatment, (3) number of relapses in separate areas within the past 24 months before treatment, (4) active MRI scans (including Gd-enhanced lesions), and (5) clinical course of MS. Results: During the observation period from 1 January 1997 to 30 May 2000 more than 44) of the patients improved by one point or more on the EDSS (confirmed after one year), 39) remained stable and 17) deteriorated. In patients with a RRMS course three or more relapses within the past 24 months preceding treatment, and at least one Gd-enhancing lesion resulted in a strong relative benefit (i.e., relative risk) of mitoxantrone effectiveness. In contrast, total number of relapses since disease onset had no impact on disease evolution and disability progression. Multivariate analysis revealed the number of relapses in separate areas within the past 24 months before treatment as the strongest predictive parameter (PB/0.001). Conclusion: Mitoxantrone is effective in improving and stabilizing patients with a worsening MS course in routine clinical practice. Several strong predictive parameters of mitoxantrone effectiveness were investigated among which the number of relapses in separate areas within the past 24 months before treatment was found to be the strongest parameter to predict clinical improvement.
Clinical impact of intravenous methylprednisolone in attacks of multiple sclerosis
Authors: Nos Carlos , Sastre-Garriga Jaume , Borrlàs Cecília , Río Jordi , Tintoré Mar , Montalban Xavier
Published: July 2004

Background: Intravenous methylprednisolone (IVMP) has been shown to hasten recovery from attacks of multiple sclerosis (MS) without altering the long term evolution of the condition; however, there is little evidence available to suggest which patients are more likely to benefit from IVMP treatment. Objective: To measure clinical change after IVMP treatment and to identify predictors of good outcome. Methods: Retrospective open-label study of medical records from 51 patients with clinically isolated syndromes or relapsing-remitting MS treated with IVMP for an acute attack (54 attacks). Results: A measurable neurological improvement was observed at one month in 44% of these attacks; the only predictor of Expanded Disability Status Scale (EDSS) change at one month was the severity of the attack. Conclusion: Attack severity predicts good response to IVMP when measured by means of EDSS.
Localization and Chemical Characterization of the Audiogenic Stress Pathway
Authors: PALKOVITS M , DOBOLYI A , HELFFERICH F , USDIN T B
Published: July 2004

Abstract: Neuronal pathways involved in stress responses to extreme somatosensory stimuli were investigated by immunostaining, viral tract tracing, and experimental brain surgery in rats. Acute audiogenic stress, which elicits an immediate marked elevation in plasma ACTH and corticosterone concentrations, was used as a model. Loud noise (105 dB, 30 min) elicited c‐fos activation within neurons in all of the components of the auditory system and stress‐sensitive brain nuclei, including corticotropin‐releasing hormone‐synthesizing parvicellular neurons in the hypothalamic paraventricular nucleus (PVN). c‐Fos activation was also seen in the medial paralemniscal nucleus in the pons (MPL) and in the subparafascicular nucleus (SPF) in the midbrain. After injection of neurotropic virus (pseudorabies, Bartha strain) into the PVN, neurons in the MPL and the parvicellular portion of the SPF were retrogradely infected. It has been shown by immunostaining that MPL and SPF neurons express a newly discovered neuropeptide, tuberoinfundibular peptide of 39 residues (TIP39). TIP39 is present in a fine neuronal network in the PVN. Audiogenic stress‐elicited c‐fos activation in TIP39‐containing neurons of the MPL and SPF. TIP39 immunoreactivity disappeared from the PVN after transection of MPL and SPF projections to the nucleus. These observations suggest that TIP39‐containing MPL and SPF neurons may participate in mediating audiogenic stress responses.
Role of GABA and Glutamate Circuitry in Hypothalamo‐Pituitary‐Adrenocortical Stress Integration
Authors: HERMAN JAMES P. , MUELLER NANCY K. , FIGUEIREDO HELMER
Published: July 2004

Abstract: GABA and glutamate play a major role in central integration of hypothalamo‐pituitary‐adrenocortical (HPA) stress responses. Recent work in our group has focused on mechanisms whereby GABAergic and glutamatergic circuits interact with parvocellular paraventricular nucleus (PVN) neurons controlling the HPA axis. GABAergic neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamus can directly inhibit PVN outflow and thereby reduce ACTH secretion. In contrast, glutamate activates the HPA axis, presumably by way of hypothalamic and brainstem projections to the PVN. These inhibitory and excitatory PVN‐projecting neurons are controlled by descending information from limbic forebrain structures, including glutamatergic neurons of the ventral subiculum, prefrontal cortex, and GABAergic cells from the amygdala and perhaps septum. Lesion studies indicate that the ventral subiculum and prefrontal cortex are involved in inhibition of HPA axis responses to psychogenic stimuli, whereas the amygdala is positioned to enhance hormone secretion by way of GABA‐GABA disinhibitory connections. Thus, it seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus. As such, these neurons are positioned to summate limbic inputs into net inhibitory tone on the PVN and may thus play a major role in HPA dysfunction seen in affective disease states and aging.
Serotonergic Stimulation of the Rat Hypothalamo‐Pituitary‐Adrenal Axis: Interaction between 5‐HT1A and 5‐HT2A Receptors
Authors: MIKKELSEN JENS D. , HAY‐SCHMIDT ANDERS , KISS ALEXANDER
Published: July 2004

Abstract: Acute stimulation of the hypothalamo‐pituitary‐adrenal (HPA) axis by selective serotonin reuptake inhibitors (SSRIs) is mediated by several postsynaptic 5‐HT receptor subtypes. Activation of 5‐HT1A and 5‐HT2A receptors increases plasma corticosterone levels, and it is likely that these receptor subtypes are central to mediating the effects of SSRIs. To study the interaction of these receptors, rats were administered with the 5‐HT1A/7 agonist 8‐OH‐DPAT (0.05 to 1.25 mg/kg), the 5‐HT2A/C agonist DOI (0.25 to 5 mg/kg), or a mixture of both compounds, and trunk blood was taken 60 min later. The two compounds given in combination produced a lower increase in corticosterone than DOI does alone. DOI and 8‐OH‐DPAT also produced a marked induction of c‐Fos in the paraventricular nucleus (PVN), but the induction was not different if the two compounds were given together. These data show that the two serotonin receptor subtypes affect the HPA axis via a central target. In conclusion, 5‐HT1A and 5‐HT2A receptors regulate corticotrophin‐releasing hormone (CRH) neurons via distinct but strongly interacting pathways, probably converging on the same neurons in the hypothalamus.
Brain Angiotensin II, an Important Stress Hormone: Regulatory Sites and Therapeutic Opportunities
Authors: SAAVEDRA J M. , ANDO H , ARMANDO I , BAIARDI G , BREGONZIO C , JEZOVA M , ZHOU J
Published: July 2004

Abstract: The presence of a brain Angiotensin II (Ang II) system, separated from and physiologically integrated with the peripheral, circulating renin‐angiotensin system, is firmly established. Ang II is made in the brain and activates specific brain AT1 receptors to regulate thirst and fluid metabolism. Some AT1 receptors are located outside the blood‐brain barrier and are sensitive to brain and circulating Ang II. Other AT1 receptors, located inside the blood‐brain barrier, respond to stimulation by Ang II of brain origin. AT1 receptors in the subfornical organ, the hypothalamic paraventricular nucleus (PVN), and the median eminence are involved in the regulation of the stress response. In particular, AT1 receptors in the PVN are under glucocorticoid control and regulate corticotrophin‐releasing hormone (CRH) formation and release. In the PVN, restraint elicits a fast increase in AT1 receptor mRNA expression. The expression of paraventricular AT1 receptors is increased during repeated restraint and after 24 h of isolation stress, and their stimulation is essential for the hypothalamic‐pituitary‐adrenal axis activation, the hallmark of the stress response. Peripheral administration of an AT1 receptor antagonist blocks peripheral and brain AT1 receptors, prevents the sympathoadrenal and hormonal response to isolation stress, and prevents the gastric stress ulcers that are a characteristic consequence of cold‐restraint stress. This evidence indicates that pharmacologic inhibition of the peripheral and brain Ang II system by AT1 receptor blockade has a place in the prevention and treatment of stress‐related disorders.