bluuebunny/crossref_metadata_2025 huggingface dataset:
A comprehensive assessment of the cost of multiple sclerosis in the United States
Authors: Whetten-Goldstein Kathryn , Sloan Frank A , Goldstein Larry B , Kulas Elizabeth D
Published: January 2007

Comprehensive data on the costs of multiple sclerosis is sparse. We conducted a survey of 606 persons with MS who were members of the National Multiple Sclerosis Society to obtain data on their cost of personal health services, other services, equipment, and earnings. Compensation of such cost in the form of health insurance, income support, and other subsidies was measured. Survey data and data from several secondary sources was used to measure costs incurred by comparable persons without MS. Based on the 1994 data, the annual cost of MS was estimated at over $34 000 per person, translating into a conservative estimate of national annual cost of $6.8 billion, and a total lifetime cost per case of $2.2 million. Major components of cost were earnings loss and informal care. Virtually all persons with MS had health insurance, mostly Medicare/Medicaid. Health insurance covered 51 per cent of costs for services, excluding informal care. On average, compensation for earnings loss was 27 per cent. MS is very costly to the individual, health care system, and society. Much of the cost (57 per cent) is in the form of burdens other than personal health care, including earnings loss, equipment and alternations, and formal and informal care. These costs often are not calculated.
Acute/relapsing experimental autoimmune encephalomyelitis: Induction of long lasting, antigen-specific tolerance by syngeneic bone marrow transplantation
Authors: Karussis Dimitrios , Vourka-Karussis Urania , Mizrachi-Koll Rachel , Abramsky Oded
Published: January 2007

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE-induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy.
Stress and coping in multiple sclerosis: exacerbation, remission and chronic subgroups
Authors: Kroencke Dawn C , Denney Douglas R
Published: January 2007

Individuals with multiple sclerosis were asked to identify stressors they had experienced over a 6-month period and the coping mechanisms employed to deal with those stressors. Subjects who reported currently experiencing an exacerbation of symptoms were compared with those in remission or in the chronic phase of their illness. Of the 61 subjects who completed the Hassles Scale, Uplifts Scale, and Ways of Coping, those classified as being in an exacerbation phase of MS were found to have significantly higher hassles scores than those in the chronic phase. A significant difference was also found in terms of a factor labeled `passive avoidant and aggressive coping' derived through a factor analysis of the Ways of Coping subscales. Subjects in the exacerbation subgroup had higher scores on this coping factor than those in the chronic subgroup. The difference in hassles scores remained significant after between-group differences in length of illness and reported number of symptoms were controlled through an analysis of covariance, although the difference in coping fell short of significance in this covariance analysis.
Lack of association of transforming growth factor (TGF)-b1 and b2 gene polymorphisms with multiple sclerosis (MS) in Northern Ireland
Authors: McDonnell G V , Kirk C W , Hawkins S A , Graham C A
Published: January 2007

Objective: To examine the influence of TGF-b genes on MS susceptibility. Background: TGF-b, of which three homologous isoforms exist (1, 2 and 3), is a strongly immunosuppressive cytokine - inhibiting expression of pro-inflammatory cytokines and blocking cytokine induction of adhesion molecules. TGF-b delays onset of EAE and TGF-b1 gene knockout mice develop fatal multifocal inflammatory disease. High TGF-b levels exist during MS remission whilst E-selectin, whose expression is inhibited by TGF-b, is found at higher levels in primary progressive disease (PPMS) and it is postulated that the unremitting course of PPMS may be due to low levels of TGF-b. Methods: Gene association studies using separate polymorphic microsatellite markers for TGF-b1 and TGF-b2 were performed, incorporating 151 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 104 PPMS patients and 159 normal controls (Nor). Forward primers were 5' end-labelled with 6-Fam, PCR products were analysed on an Applied Biosystems 373A fluorescent fragment analyser and Genescan 672 software was used for allele sizing. Results: No significant differences existed in allele frequencies between either MS group and controls regarding the TGF-b1 marker: RR/SPMS vs Nor (P=0.48, df=8); PPMS vs Nor (P=0.34, df=8). Similarly there were no associations demonstrated with the TGF-b2 marker: RR/SPMS vs Nor (P=0.24, df=2); PPMS vs Nor (P=0.53, df=2). Conclusion: These data indicate that TGF-b1 and b2 genes are not loci influencing MS susceptibility, either RR/SPMS or PPMS, in this population.
Autoimmunity in multiple sclerosis: study of a wide spectrum of autoantibodies
Authors: Spadaro M , Amendolea M A , Mazzucconi M G , Fantozzi R , Di Lello R , Zangari P , Masala C
Published: January 2007

The aim of this study was to assess the frequency of organ- and nonorgan-specific autoantibodies in MS patients and evaluate whether the presence of autoantibodies is an indicator of disease activity and/or a prognosis factor. One hundred and five definite MS patients in different stages and with different course and 75 blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl, SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P50.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically higher in patients than in controls. Circulating ANCAs were found in seven MS, a never reported finding. An early onset of MS (520 years) was associated with a lower autoantibody frequency (P50.01). Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P50.05) or benign (P50.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P50.001). A generalised immune dysregulation occurs in MS patients, mostly during the acute stages and in the progressive courses, involving activation of both autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.
Effects of phosphodiesterase inhibitors on cytokine production by microglia
Authors: Yoshikawa Minka , Suzumura Akio , Tamaru Tsukasa , Takayanagi Tetsuya , Sawada Makato
Published: January 2007

Type III and IV phosphodiesterase inhibitors (PDEIs) have recently been shown to suppress the production of TNF-α in several types of cells. In the present study, we have shown that all the types of PDEIs, from type 1- to V-specific and non-specific, suppress the production of TNF-α by mouse microglia stimulated with lipopolysaccharide (LPS) in a dose-dependent manner. Certain combinations of three different types of PDEIs synergistically suppressed TNF-α production by microglia at a very low concentration (1 μM). Since some PDEIs reportedly pass through the blood-brain barrier (BBB), the combination of three PDEIs may be worth trying in neurological diseases, such as multiple sclerosis and HIV-related neurological diseases in which TNF-α may play a critical role. Some PDEIs also suppressed interleukin-1 (IL-1) and IL-6 production by mouse microglia stimulated with LPS. In contrast, the production of IL-10, which is known to be an inhibitory cytokine, was upregulated by certain PDEIs. The suppression of TNF-α and induction of IL-10 were confirmed at the mRNA level by RT - PCR. PDEIs may be useful anti-inflammatory agents by downregulating inflammatory cytokines and upregulating inhibitory cytokines in the central nervous system. (CNS).
Lesion development in Marburg's type of acute multiple sclerosis: from inflammation to demyelination
Authors: Bitsch A , Wegener C , da Costa C , Bunkowski S , Reimers C D , Prange H W , Brück W
Published: January 2007

We report a patient who suffered from acute inflammatory CNS demyelination and underwent two consecutive diagnostic stereotactic brain biopsies during the early disease course. The first lesion was drawn 33 days after the onset of disseminated neurological symptoms. Macrophages and T lymphocytes diffusely infiltrated small vessel walls and the white matter. mRNA for tumor necrosis factor alpha (TNFa) and inducible nitric oxide synthase (iNOS) was abundantly expressed. Myelin sheaths were entirely preserved. The second biopsy 76 days later showed confluent demyelinating lesions with a diffuse infiltration of macrophages that were positive for myelin debris, activation markers and TNFa and iNOS mRNA. IgG and C9neo deposits were found along myelin sheaths. The patient had received intravenous immunoglobulins (IVIG) prior to biopsy. Findings from this single patient affirm that demyelination follows the migration of inflammatory cells from the circulation into the white matter with subsequent inflammation and demyelination. Inflammation alone may be sufficient to cause significant clinical deficits without demyelination. Inflammatory mediators such as TNFa and NO are involved at very early stages in the pathogenetic process. IVIG treatment may lead to the deposition of immunoglobulins and to the activation of the complement cascade, but the clinical relevance of this particular finding remains uncertain.
Candidate autoantigens in multiple sclerosis
Authors: Schmidt Stephan
Published: January 2007

Multiple sclerosis is an inflammatory demyelinating CNS disease of putatively autoimmune origin. Novel models of experimental autoimmune encephalomyelitis (EAE) have demonstrated that T cells specific for various myelin and even nonmyelin proteins are potentially encephalitogenic. The encephalitogenic T cell response directed against different CNS antigens not only determines the lesional topography of CNS inflammation but also the composition of the inflammatory infiltrates. The heterogeneity of the lesional distribution seen in EAE might therefore be useful for the understanding of the various clinical subtypes seen in MS. In this review the possible candidate autoantigens in MS are discussed with special regard to the human T cell and B cell responses against various myelin and nonmyelin proteins.
Biological markers in body fluids for activity and progression in multiple sclerosis
Authors: Sùrensen Per Soelberg
Published: January 2007

Reliable biological markers in body fluids for disease activity and progression are important for our understanding of the pathophysiology and therapeutic decisions in various subtypes of multiple sclerosis. Sampling from body fluids such as cerebrospinal fluid, blood, and urine constitutes the problem that the local immuno-inflammatory process takes place in the central nervous system whereas the disease activity is only to some extent reflected in the systemic immune compartment. Promising results have been obtained in studies of adhesion molecules, pro-inflammatory cytokines, co-stimulatory molecules and neopterin as markers of disease activity in relapsing-remitting multiple sclerosis. However, these results apply to groups of patients but not necessarily to individual patients. Currently no single body fluid marker is sufficiently correlated to disease activity to be used in the individual patient in monitoring disease activity, progression, or therapeutic effects.
The effects of anxiety on psychiatric morbidity in patients with multiple sclerosis
Authors: Feinstein A , O'Connor P , Gray T , Feinstein K
Published: January 2007

Our objective was to assess the point prevalence and effects of clinically significant anxiety in patients with Multiple Sclerosis (MS). One hundred and fifty two consecutive patients with MS attending an outpatient clinic underwent neurological examination and were assessed for psychopathology with the Hospital Anxiety and Depression Scale, the 28 item General Health Questionnaire and a questionnaire probing suicidal thoughts or intent. Clinically significant anxiety, either with or without depression, was endorsed by 25% of patients, three times the rate for depression. Females were significantly more anxious than males. Anxiety co-morbid with depression, rather than anxiety or depression alone, was associated with increased thoughts of self harm, more somatic complaints and greater social dysfunction. Patients with increased psychopathology were not more likely to be taking psychotropic medication. The results provide preliminary evidence that anxiety, which may be often overlooked clinically, is a frequent accompaniment to depression, thereby adding to the morbidity associated with MS. The implications of the findings to MS patients' quality of life are emphasised.
Increased urinary nitric oxide metabolites in patients with multiple sclerosis correlates with early and relapsing disease
Authors: Giovannoni Gavin , Silver N C , O'Riordan J , Miller R F , Heales S J.R. , Land J M , Elliot M , Feldmann M , Miller D H , Thompson E J
Published: January 2007

Nitric oxide (•NO) has been implicated in the immunopathogenesis of MS as a potential mediator of neuronal loss. To investigate the role of .NO in the development of progressive disease we measured the .NO metabolites (nitrate and nitrite) and neopterin, in the urine of 129 patients with demyelinating disease (DD): 23 with clinically isolated syndromes compatible with demyelination and in 46 relapsing remitting (RR) and 60 patients with progressive MS. Eighty-nine of these 129 patients underwent Gd-enhanced MRI. In addition 58 normal control subjects (NC), 19 AIDS and 35 rheumatoid arthritis (RA) patients were studied. Patients with DD, AIDS and RA had significantly elevated urinary nitrate plus nitrite (nit: creat.urine) and neopterin (neopt: creat.urine) to creatinine ratios compared to NC subjects. (Median[25th-75th%] nit: creat.urine: NC=1183[962-1365] vs DD=1245[875-2403], AIDS=1686[1231-2531], and RA=1950[1214-2726] mmol/mol, P50.001 and median[25th-75th%] neopt: creat.urine: NC=99[76-151] vs DD=163[119-266], AIDS=972[653-1456], and RA=389[257-623] mmol/mol, P50.001). Patients with early DD and RR MS had significantly elevated nit: creat.urine compared to patients with progressive MS (nit: creat.urine: 1612[1020-2733] vs 1159[790-1641] mmol/mol, P=0.006). The nit: creat.urine and neopt: creat.urine did not correlate with clinical relapse or MRI activity. Excretion of .NO metabolites is increased in patients with early or relapsing-remitting disease. .NO appears to be a double-edged sword, mediating tissue damage and modulating complex immunological functions which may be protective in MS.
Disease steps in multiple sclerosis: a longitudinal study comparing Disease Steps and EDSS to evaluate disease progression
Authors: Hohol M J , Orav E J , Weiner H L
Published: January 2007

Clinical assessment of outcome in Multiple Sclerosis (MS) patients is problematic since the disease can affect different aspects of the central nervous system and follow a variable course. Recently, we developed Disease Steps, a simple approach for evaluating disease progression. Previously, we found that Disease Steps was easy to use, had uniformly distributed scores and low inter-rater variability. Our current objective was to test the long-term use of Disease Steps together with the most widely utilized clinical outcome measure in MS, the Expanded Disability Status Scale (EDSS) in assessing clinical progression. Over 4 years, 804 patients were classified using both EDSS and Disease Steps. Each patient was assessed at least twice. Follow-up results included annual status and time-to-event analysis examining median staying times within a level of Disease Steps or EDSS. We found that the two scales behaved similarly and correlated strongly with each other. For both Disease Steps and EDSS, patients with milder levels of disability and relapsing-remitting disease demonstrated a higher likelihood of changing scores over time and shorter median staying times compared to more disabled, chronic progressive patients. These findings have important implications for patient selection in clinical trials and for the design of future measurements of clinical outcome in MS. Furthermore, Disease Steps may serve as a simple, practical tool for the nonspecialty neurologist to follow patients over time and serve as a guide in therapeutic decision making. Our findings further document the general progressive nature of MS when a large cohort is followed in an MS specialty clinic over time.
The association of the human herpesvirus-6 and MS
Authors: Friedman J E , Lyons M J , Cu G , Ablashl D V , Whitman J E , Edgar M , Koskiniemi Marjaleena , Vaheri Antti , Zabriskie J B
Published: January 2007

Given the clinical and pathological nature of multiple sclerosis (MS), a viral infection has long been hypothesized as part of the etiology. In this study we investigated the possibility that the human herpesvirus-6 (HHV-6) is present in a dormant or active phase in the tissue of MS patients, specifically oligodendrocytes. Using PCR assays of MS and non-MS brain sections with primers prepared against the HHV-6 structural protein 101, the results demonstrated that 36% of MS brains were positive for the virus, while 13.5% of non-MS brains were positive. Antibody to the HHV-6 structural protein was also used in immunohistochemical experiments in brain tissue. 47% (7/15) of MS brains were positive for HHV-6, whereas 0/16 controls were positive. In addition, MS patients demonstrated high immune reactivity to this virus, even when compared to auto-immune diseases, which might cause polyclonal activation. Sera obtained from MS and control patients revealed that the IgM response to the HHV-6 virus was significantly elevated in 80% patients compared to 16% non-MS controls, P5.001. The above experiments strongly suggest that a significant number of MS brain samples contain HHV-6 antigens and genomic fragments in a dormant or active phase compared to control specimens and that MS patients mount a brisk, early IgM response.
A profile of multiple sclerosis: The New York State Multiple Sclerosis Consortium
Authors: Jacobs L D , Wende K E , Brownscheidle C M , Apatoff B , Coyle P K , Goodman A , Gottesman M H , Granger C V , Greenberg S J , Herbert J , Krupp L , Lava N S , Mihai C , Miller A E , Perel A , Smith C R , Snyder D H ,   The New York State Multiple Sclerosis Consortium
Published: January 2007

We have obtained a current profile of multiple sclerosis (MS) in New York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.
Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral arterial disease
Authors: Brass Eric P , Hiatt William R
Published: January 2007

Peripheral arterial disease (PAD) is associated with an increased risk of overall cardiovascular mortality, and substantial morbidity resulting from claudication. While the initial disease process is clearly the result of atherosclerosis in the arterial circulation of the limb, altered hemodynamics do not completely explain the pathophysiology of claudication. Work from several laboratories has demonstrated secondary changes in the skeletal muscle of patients with PAD which are consistent with the presence of an acquired metabolic myopathy in these patients. Key findings include an alteration in the expression of mitochondrial enzymes, the accumulation of metabolic intermediates, altered regulation of mitochondrial respiration, increased oxidative stress, and the presence of somatic mutations in the mitochondrial genome. Understanding the metabolic changes associated with PAD is important in understanding the pathophysiology of claudication and in the development of novel therapeutic strategies.
Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life
Authors: Gresele P , Migliacci R , Sante G Di , Nenci GG ,   CRAMPS Investigator Group
Published: January 2007

The main aim of medical treatment for intermittent claudication (IC) is the reduction of mortality and morbidity from ischemic cardiovascular disease. However, symptomatic treatment with the aim of improving exercise performance and the overall quality of life may also be an important target of the clinical management of patients with intermittent claudication. Cloricromene, a drug with antithrombotic and anti-ischemic activities, has previously shown some promising results in patients with claudication. We have carried out a clinical trial to assess the effect of cloricromene on the claudication distance and on the quality of life of patients with IC chronically treated with aspirin. A total of 159 patients with IC, Stage II (Fontaine), were enrolled in a double-blind, randomized, prospective, multicenter study comparing cloricromene (100 mg orally b.i.d.) or an identical placebo for 6 months. All patients received 160 mg/day aspirin. The primary end-point was the improvement of initial claudication distance (ICD) at 6 months as measured by a standardized treadmill test. The secondary end-points were the absolute claudication distance (ACD) at 6 months, the percentage of patients defined as responders to treatment (improvement of ICD of at least 40%), changes in the ischemic window (IW), quality of life as assessed by the SF-36 questionnaire, and the occurrence of major cardiovascular events. The ICD increased in both treatment groups, with a non-significant difference at 6 months in favor of cloricromene of +12.3 m. The ACD, percentage of responders to treatment and ischemic window also improved in both groups with a slight, non-significant trend in favor of cloricromene. Pretreatment quality of life scores showed only a slight worsening compared with an age-matched, healthy population and did not change upon treatment. A post hoc subgroup analysis showed a significant benefit from cloricromene in patients with an ICD at enrollment higher than the median of the patient population. In conclusion, treatment with cloricromene for 6 months does not significantly improve claudication in patients with Stage II Fontaine peripheral arteriopathy chronically treated with aspirin. An improvement of 40-60 m in the ICD on a standardized treadmill test does not translate into a self-perceived improvement in the quality of life as assessed by the SF-36 questionnaire.
Lack of functional benefits following infrainguinal bypass in peripheral arterial occlusive disease patients
Authors: Gardner Andrew W , Killewich Lois A
Published: January 2007

This study aimed to determine whether peripheral arterial occlusive disease (PAOD) patients with critical limb-threatening ischemia experienced functional benefits following lower extremity revascularization. Twenty ambulatory patients (aged 68 - 7 years) underwent infrainguinal revascularization to alleviate their symptoms. Peripheral hemodynamic and functional measures were obtained on each patient 1 week prior to and 3-4 months following revascularization. Critical limb-threatening ischemia was alleviated by surgery in all patients because the ankle/brachial index (ABI) increased 133% (p, 0.001) from 0.33 6 0.06 to 0.77 6 0.09. Despite the marked peripheral hemodynamic improvement following revascularization, little gains were noted in functional measures. The 6-min walking distance was unchanged (p = 0.739) from 85 6 9 m to 101 6 11 m. Additionally, the free-living daily physical activity, measured by an accelerometer worn over a 2-day period, was unchanged (p = 0.996) from 214 6 46 kcal/day to 215 6 83 kcal/day. In contrast, self-perceived ambulatory function improved by 142% to 271% (p, 0.001), and self-perceived physical activity increased 134% to 156% (p, 0.001). In conclusion, limb salvage following infrainguinal bypass does not translate into improvements in measured ambulation or in measured physical activity in PAOD patients, even though the patients perceive these measures to be better.
In vivo measurement of cerebral blood flow: a review of methods and applications
Authors: Griffiths Paul D , Hoggard N , Dannels Wayne R , Wilkinson Iain D
Published: January 2007

This article reviews the concepts of cerebral blood flow for the clinician involved in the management of patients with carotid stenosis and/or ischaemic stroke. Methods of assessing cerebral blood flow in vivo using nuclear medicine, magnetic resonance and X-ray computed tomography are described. Applications of magnetic resonance and X-ray computed tomographic methods are reviewed and illustrated by examples from the authors' radiological practice.
Vascular viewpoint
Authors: Anand Sonia S
Published: January 2007

Question: Are oral anticoagulants (target INR 3.0-4.5) more effective than aspirin (80 mg) in the prevention of infrainguinal bypass-graft occlusion?

Population: Patients who required infrainguinal bypass graft surgery (venous or synthetic grafts) for obstructive arterial disease.

Design and methods: Randomized, open, clinical trial. A total of 1339 patients randomized to oral anticoagulants (target INR = 3.0-4.5) and 1351 to aspirin (80 mg/day). Treatment was started within 5 days of surgery. Primary outcome was graft occlusion defined as clinical examination and Doppler or duplex ultrasound evaluation and angiography when indicated. Mean length of follow-up was 21 months. Blinded adjudication of primary and secondary outcomes. Intention to treat analysis. Pre-specified subgroup analysis of primary outcome by graft type.

Results: In all, 182/1326 (13.7%) discontinued oral anticoagulants and 190/1324 (14.3%) discontinued aspirin. A total of 308/1326 (23.2%) on oral anticoagulants vs 322/1324 (24.3%) on aspirin had graft occlusion; relative risk = 0.95 (95% CI: 0.82-1.11). Secondary outcome composite of cardiovascular death, myocardial infarction, stroke, and amputation was 248/1326 (18.7%) on oral anticoagulants vs 275/1324 (20.8%) on aspirin; relative risk = 0.89 (95% CI: 0.75-1.06). Major hemorrhage was 108/1326 (8.1%) on oral anticoagulants vs 56/1324 (4.2%) on aspirin; relative risk = 1.96 (95% CI: 1.42-2.71). For vein grafts (n = 1546) the relative risk of occlusion was 0.69 (95% CI: 0.54-0.88) on oral anticoagulants vs aspirin. For non-vein grafts (n = 1104) the relative risk of occlusion was 1.26 (95% CI: 1.03-1.55) on oral anticoagulants vs aspirin. The statistical test for interaction between these subgroups was significant (p = 0.002).

Conclusion: High intensity warfarin (INR: 3-4.5) does not significantly reduce graft occlusion after infrainguinal bypass compared with aspirin. Oral anticoagulants are associated with a significant increase in major bleeding episodes. Oral anticoagulants and aspirin may alter the pathogenesis of graft re-occlusion differently depending on graft type.
Claudication does not always precede critical leg ischemia
Authors: Mätzke Sorjo , Lepäntalo Mauri
Published: January 2007

Prevalence of intermittent claudication is often used to calculate the prevalence of critical leg ischemia (CLI), a more severe form of peripheral arterial disease (PAD). Although this logical course of the disease is intellectually appealing, not all patients with CLI have experienced any symptoms of previous claudication. A total of 100 consecutive patients with objective evidence of critical ischemia, as evaluated by non-invasive testing in the authors’ vascular laboratory, were subjected to a structured interview to evaluate how often peripheral arterial disease is presented with symptoms of CLI as the initial complaint. In all, 37 patients had never experienced claudication prior to the development of CLI. Furthermore, 12 of 63 patients who suffered from previous claudication did not have any claudication symptoms at the time of the development of CLI. Of the 37 patients with CLI as the first sign of PAD, 20 had diabetes - four of whom with manifest diagnosed neuropathy. The patients without previous claudication more frequently had ulcers as the initial symptom of CLI (89%) than those with claudication (59%), whose disease first progressed to rest pain. Altogether, 25 patients did not walk enough to develop symptoms of claudication. In conclusion, every patient presenting with symptoms potentially related to CLI should undergo vascular laboratory measurements regardless of whether he/she has a history of claudication or not. This is especially true in limbs with unhealed skin lesions.
Genetic factors associated with endothelial dysfunction affect the early onset of coronary artery disease in Korean males
Authors: Lee Won-Ha , Hwang Tae-Hong , Oh Goo Taeg , Kwon Sung Uk , Choi Yoon-Ho , Park Jeong-Euy
Published: January 2007

The maintenance of balance between nitric oxide (NO) and the superoxide anion is required for proper functioning of the endothelium. To investigate the relationship between genetic factors associated with endothelial function and the development of coronary artery disease (CAD), endothelial nitric oxide synthase ( ecNOS) gene a/b polymorphism and NADH/NADPH oxidase p22 phox gene C242T polymorphism were examined in 305 Korean male CAD patients and 215 healthy male control subjects. The β-fibrinogen gene H1/H2 polymorphism was also analyzed. Both ecNOS a/b and p22 phox C242T polymorphisms were found to be associated with the development of CAD in the study population ( p = 0.020 and 0.011, respectively). When the association was analyzed by age, statistical significance was retained only in those <51 years ( p = 0.021 and 0.025 for the a/b and the C242T polymorphism, respectively) and not in those >51 years of age ( p =0.155 and 0.278 respectively). However, the distribution of the β-fibrinogen H1/H2 genotypes was not found to be associated with the development of CAD in either the ≤50 ( p = 0.611) or >50 groups ( p = 0.188). The ecNOS gene a/b polymorphism and the NADH/NADPH oxidase p22 phox gene C242T polymorphism were found to be significantly associated with the development of CAD in Korean male patients less than 51 years old.
Cholesterol-induced upregulation of angiotensin II and its effects on monocyte-endothelial interaction and superoxide production
Authors: Niebauer Josef , Tsao Philip S , Lin Patrick S , Pratt Richard E , Cooke John P
Published: January 2007

Atherogenesis involves an early endothelial dysfunction hallmarked by elevated free radical production and increased adhesiveness for monocytes. It was hypothesized that activation of the tissue renin angiotensin system may contribute to the endothelial alteration. To test this hypothesis, thoracic aortae were isolated from normocholesterolemic (NC; n = 6) and hypercholesterolemic (HC; n = 6; diet: 0.5% cholesterol; 6 weeks) New Zealand white rabbits, and incubated for 2 h with the angiotensin II (Ang II) receptor antagonist Sar-1, Ile-8-Ang II, the antioxidant pyrolidine dithiocarbamate (PDTC) and the protein kinase C (PKC) antagonist staurosporin. Superoxide production from aortic segments was measured by lucigenin-enhanced chemiluminescence. In comparison to the normocholesterolemic state, hypercholesterolemia led to a significant increase in superoxide production (221 ± 44%, p ≤ 0.02); this was reduced by ex vivo treatment of the vessel segment with Ang II-antagonist (to 130 ± 29%; p ≤ 0.04 vs HC), or PKC-antagonist (to 86 ± 26%; p ≤ 0.001 vs HC), or PDTC (to 103 ± 27%; p ≤ 0.02 vs HC). Monocyte-endothelial interaction was assessed by functional binding assay. When compared to normocholesterolemic rabbits, hypercholesterolemia led to a twofold increase in monocyte binding (74 ± 13 vs 37 ± 4 monocytoid cells per high power field (m/hpf); p ≤ 0.03). The Ang II-antagonist and the PKC-antagonist led to a normalization of monocyte-endothelial binding (Ang II-antagonist: 37 ± 9 m/hpf; PKC-antagonist: 41 ± 17 m/hpf; p ≤ 0.05). In conclusion, these results indicate that hypercholesterolemia activates the tissue renin angiotensin system, which results in an increased endothelial production of superoxide and monocyte adhesiveness. Ang II-antagonist inhibits free radical production and monocyte adhesion through a mechanism which may include PKC.
Effects of stenting on adjacent vascular distensibility and neointima formation: role of nitric oxide
Authors: Schwarzacher Severin P , Tsao Philip S , Ward Michael , Hayase Moto , Niebauer Josef , Cooke John P , Yeung Alan C
Published: January 2007

Intravascular stents increase long-term patency but their effects on the vascular mechanics of adjacent segments have not been studied. In this study, stents were deployed in the rabbit abdominal aorta after 1 week of normal diet, 1% cholesterol diet or 1% cholesterol diet with l-nitro arginine (l-NA 60 mg/l water). Intravascular ultrasound showed a small distal decrease in vessel distensibility (area/pressure * 100) before stenting. Distensibility was almost abolished by stenting (0.12 ± 0.01, p ≤ 0.001), but was increased proximal to the stent and decreased distal to the stent both acutely (proximal: 1.18 ± 0.10 vs distal: 0.65 ± 0.06, p ≤ 0.001), and at 4 weeks (proximal: 1.05 ± 0.08 vs distal: 0.37 ± 0.07, p ≤ 0.001). Nitric oxide (NO) activity was enhanced proximal to and within the stent, and remained constant distal to the stent, (versus control, proximal: 57 ± 23%, stent: 136 ± 35%, distal: 2 ± 12%, p ≤ 0.01). The I/M ratio was significantly higher proximal to and within the stent than in the distal segment (proximal: 0.40 ± 0.10, stent: 0.37 ± 0.12, distal: 0.12 ± 0.11, p ≤ 0.01). NO blockade with l-NA prevented hyperdistensibility proximally, and significantly increased the I/M ratio within the stent and distally (stent: 0.81 ± 0.19, distal: 0.30 ± 0.10, p ≤ 0.05) but not proximally (0.38 ± 0.09). In conclusion, aortic stenting increases proximal vascular distensibility and intimal lesion formation. Nitric oxide blockade augments intimal growth within but not proximal to the stent.
Total serum homocysteine - a predictor of extracranial carotid artery stenosis in male patients with symptomatic peripheral arterial disease
Authors: Mueller Thomas , Furtmueller Bernhard , Aigelsdorfer Johannes , Luft Christian , Poelz Werner , Haltmayer Meinhard
Published: January 2007

High total serum homocysteine (tHcy) concentrations are associated with an increased risk of carotid artery disease in the general population. Since patients with peripheral arterial disease (PAD) have a threefold risk of cerebrovascular morbidity compared to individuals free of PAD, and since the total neurological event rate is associated with a ≥50% lumen reduction in extracranial carotid arteries, it was tested whether tHcy is a predictor of internal carotid artery stenosis in patients with symptomatic PAD. A total of 443 consecutive male PAD patients without previous carotid surgery/stenting were studied. In all, 100 patients with PAD had an internal carotid artery stenosis ≥50%. Of the remaining 343 patients, 100 individuals matched for age (±2 years) and diabetes served as controls. The extent of carotid stenosis was evaluated with color duplex measurement; tHcy was determined by high-performance liquid chromatography. Cases displayed a significantly higher median fasting tHcy level (17.0 μmol/l) than controls (13.7 μmol/l, p = 0.001). Multivariate analysis showed that tHcy ( p = 0.036) was an independent predictor of internal carotid artery stenosis ≥50% in PAD patients, representing an odds ratio of 1.32 (95% CI, 1.02-1.72) for an increment of 5 μmol/l. In the present study, high tHcy was an independent risk factor for an internal carotid artery stenosis ≥50% in patients with PAD. Since PAD patients suffer a threefold risk of stroke compared to healthy individuals, a simple vitamin substitution in PAD patients may reduce the occurrence of internal carotid artery stenosis and therefore diminish the relatively high rate of cerebrovascular events in this population.
Small and large artery elasticity indices in peripheral arterial occlusive disease (PAOD)
Authors: Duprez DA , De Buyzere ML , De Bruyne L , Clement DL , Cohn JN
Published: January 2007

In peripheral arterial occlusive disease (PAOD), arterial compliance of the central arteries has been reported to be reduced. It is, however, not clear whether, in PAOD, decreased arterial compliance is also accompanied by similar changes in the peripheral arteries. Therefore the aim of the study was to determine the large (C1) and small (C2) artery elasticity indices in PAOD and their relations to its well-accepted characteristics (ankle-brachial index, ABI; pulse pressure, PP; absolute claudication distance, ACD). A total of 43 patients with PAOD (mean age 68 ± 9 years; ABI of the limiting leg 0.65 ± 0.14; SBP (systolic blood pressure) 149 ± 20 mmHg, and ACD 488 ± 187 m) were enrolled as well as 16 control subjects of comparable age (69 ± 4 years) and blood pressure (SBP 147 ± 27 mmHg). All subjects underwent non-invasive pulse wave analysis in order to determine arterial compliance of the aorta and major side branches (C1) and of the distal circulation (C2), using a modified Windkessel model. In PAOD, both C1 (1.41 ± 0.56 ml/mmHg) and C2 (0.023 ± 0.012 ml/mmHg) were comparable to values in an age and blood pressure-matched control group (C1, 1.25 ± 0.66 ml/mmHg; C2, 0.027 ± 0.008 ml/mmHg). C1 was significantly correlated with ACD ( r = 0.36, p = 0.02), PP ( r =-0.33, p < 0.02) and only borderline with ABI ( r = 0.28, p = 0.07). C2 was correlated with PP ( r =-0.38, p < 0.01), ABI ( r = 0.36, p < 0.02) but not with ACD. Large (C1) and small (C2) artery elasticity indices in PAOD were decreased but comparable to values in an elderly group with isolated systolic hypertension. Moreover, C1 and C2 correlated with markers (ABI and PP) of severity of vascular disease.
Atherothrombosis - the neurologist’s point of view
Authors: Leys Didier
Published: January 2007

Patients with peripheral arterial disease (PAD) have an increased risk of cerebral ischaemia, but many transient ischaemic attacks are not recognized by patients, or by physicians who are not neurologists. Similarly, PAD is common in stroke patients, but often remains unrecognized by neurologists. Major long-term risks in patients with cerebral ischaemia due to atherosclerosis are myocardial infarction and recurrence of stroke. Neurologists should consider concomitant PAD when choosing a treatment strategy. Patients with PAD need to be educated about their risk for cerebral ischaemic events, and physicians caring for PAD patients need to identify those individuals who may require carotid surgery. The appropriate strategy for prevention of stroke in PAD patients consists of optimal management of risk factors for stroke (smoking, arterial hypertension, hypercholesterolaemia), antiplatelet therapy with clopidogrel as first-choice treatment, and carotid surgery in patients with high-grade stenosis of the internal carotid artery who are at low risk for surgery.
Forearm blood flow measured by venous occlusion plethysmography in healthy subjects and in women with postmastectomy oedema
Authors: Stanton Anthony WB , Holroyd Ben , Northfield John W , Levick J Rodney , Mortimer Peter S
Published: January 2007

A chronic swelling of the arm may develop following damage to axillary lymph vessels during breast cancer treatment. Certain unusual pathophysiological features of postmastectomy oedema indicate that factors additional to lymphatic damage are important. One factor postulated previously is a haemodynamic abnormality. Forearm blood flow was therefore measured by venous occlusion plethysmography using both a conventional mercury strain gauge and a newer optical volumeter (Perometer®). The latter was initially assessed in healthy subjects.

When forearm blood flow was measured using the two methods simultaneously, the strain gauge and Perometer®did not differ significantly for healthy or oedematous arms. Dominant and non-dominant arm blood flow in healthy subjects was similar but with greater variation between sides with the Perometer®. Using the strain gauge, blood flow in the oedematous arm (2.51 6 1.33 ml/100 ml per min) was significantly lower than in the opposite unaffected arm (3.77 6 2.29 ml/100 ml per min; p = 0.026). The Perometer®results showed a similar but nonsignificant trend (p = 0.105). Taking into account the greater limb volume on the affected side, total forearm blood flow was essentially the same in each arm (unaffected: 40.72 6 28.70 ml/min; oedematous: 41.78 6 22.11 ml/min).

The reduced blood flow per unit volume of arm was therefore likely to be due to a simple `dilution' effect of the increase in volume. The results indicate that it is unlikely that raised blood flow contributes to oedema formation, contrary to the haemodynamic concept.
Clinical overview of venous thromboembolism
Authors: Goldhaber Samuel Z
Published: January 2007

Pulmonary embolism and deep venous thrombosis constitute a major cause of vascular illness in the USA. The mortality rate of pulmonary embolism is high, and recurrent events frequently occur. The optimal duration of treatment with anticoagulation is unknown. Diagnostic work-ups now often include plasma D-dimer levels and echocardiography in addition to conventional lung scanning and pulmonary angiography. Among patients with right ventricular dysfunction, thrombolytic therapy is being used more often because this strategy may improve overall prognosis. Since venous thromboembolism is difficult to diagnose and expensive to treat, prophylaxis against this disease is of paramount importance.
Early discharge strategies following venous thrombosis
Authors: Büller Harry R , Kraaijenhagen Roderik A , Koopman Maria MW
Published: January 2007

Low-molecular-weight heparin therapy is administered subcutaneously, not intravenously. This has made possible the management of selected patients who have acute deep venous thrombosis as outpatients. Others can be treated with an abbreviated several day hospitalization rather than the conventional 5 or more hospital days needed for administration of continuous intravenous unfractionated heparin. Two large studies, Tasman and a Canadian trial, have demonstrated the efficacy and safety of low-molecular-weight heparin in this setting. Now, the task is to develop guidelines for widespread application of these findings to daily clinical practice. However, successful home treatment will require intensive patient education as well as an extensive infrastructure of supportive nursing and physician services. Careful patient follow-up will be crucially important.
Postdischarge prophylaxis for venous thromboembolism among high-risk surgery patients
Authors: Agnelli Giancarlo
Published: January 2007

The role of pharmacological prophylaxis against venous thromboembolism in high-risk surgical patients is straightforward during hospitalization but controversial after hospital discharge. Clinical trials based upon venography-detected deep vein thrombosis (DVT), yield high DVT rates which may not be clinically relevant, since most cases are asymptomatic. On the other hand, clinical surveys based upon clinically overt venous thromboembolism yield low DVT rates that underestimate the problem. If postdischarge prophylaxis is used, oral anticoagulants may be more cost-effective than low-molecular-weight heparins. However, optimal strategies for venous thromboembolism prophylaxis after hospital discharge will not be definitively provided until large studies are performed with sufficient power to detect clinically relevant endpoints such as symptomatic DVT or pulmonary embolism.
Percutaneous venous interventions
Authors: Bravo Stephen M , Reinhart Robert D , Meyerovitz Michael F
Published: January 2007

Percutaneous procedures by interventional radiologists are becoming an increasingly frequent part of the overall care of patients with complex venous thrombotic diseases. Inferior vena caval filters are used in the setting of failed or contraindicated anticoagulation. Catheter-directed thrombolysis is considered for patients with extensive iliofemoral deep venous thrombosis. Venous angioplasty is often indicated for patients with dialysis shunt venous stenoses, upper extremity venous stenoses and for stenoses within venous bypass grafts. Venous stenting is often employed following angioplasty to ensure long-term procedural success. Finally, suction and mechanical thrombectomy and embolectomy are relatively new procedures that are available to optimize patient management.