bluuebunny/crossref_metadata_2025 huggingface dataset:
The Danish Multiple Sclerosis Registry: a 50-year follow-up
Authors: Koch-Henriksen Nils
Published: January 2007

The Danish Multiple Sclerosis Registry was established in 1948 in continuation with a nationwide survey of the prevalence of Multiple Sclerosis (MS) in Denmark. The register has since collected information on MS patients from all Danish departments of neurology, practising neurologists, MS rehabilitation centres, the National Patient Registry, the Danish MS Society, and departments of neuropathology. The registry is linked with the Danish Central Population Registry. The completeness has been estimated at more than 90%. All cases are reclassified by two neurologists as to diagnosis and year of onset. 12 070 cases with a confirmed diagnosis of MS are kept in the databases. They were prevalent in 1949 or have had onset in the period 1948-1993. The registry is continuously updated with new information on registered cases and new cases. The crude average annual incidence rate 1980-89 was 4.99/105; the prevalence rate was 112/105 by 1 January 1990. Cross-linking with other registers have enabled analytical prospective epidemiological studies, and the registry has provided population based unbiassed samples of patients for a number of clinical studies.
Type I interferons and the quality of life of multiple sclerosis patients. Results from a clinical trial on interferon alfa-2a
Authors: Nortvedt M W , Riise T , Myhr K M , Nyland H I , Hanestad B R
Published: January 2007

The objective of the study was to examine whether the beneficial effect of treatment of interferon alfa-2a on multiple sclerosis seen by magnetic resonance imaging is reflected in a corresponding improvement in the quality of life (QoL) and to address the impact of adverse events related to this treatment on the QoL. The study was a randomised double-blinded placebo-controlled treatment trial including 97 relapsing-remitting multiple sclerosis patients. Thirty-two patients received 4.5 MIU recombinant interferon alfa-2a, 32 patients received 9.0 MIU recombinant interferon alfa- 2a and 33 patients received placebo treatment for 6 months. All patients were followed up 6 months after end of treatment. QoL was assessed according to the eight scales of the SF-36 Health Survey and measured at baseline, month 3, 6 and 12. The effect found on MRI was not reflected in a corresponding change in the QoL. We found a relationship between the presence of new enhancing lesions and reduced QoL among the placebo patients, whereas this was not found among the patients treated with interferon. The presence of the adverse events fatigue, myalgia, headache and weakness were significantly negatively correlated to several of the QoL dimensions. Conclusively, the treatment with interferon alfa- 2a does not seem to improve the patients' QoL after 6 months of treatment, in spite of a marked effect measured by MRI. The treatment is followed by adverse events that negatively affected the QoL.
Gait abnormalities in minimally impaired multiple sclerosis patients
Authors: Benedetti M G , Piperno R , Simoncini L , Bonato P , Tonini A , Giannini S
Published: January 2007

Subclinical evidence of gait abnormalities were identified in a group of seven patients with Multiple Sclerosis, EDSS scored 0-2, without functional limitations. A movement analysis technique was used to identify gait parameters indicative of impaired motor function during walking. Abnormalities related primarily to time-distance parameters (reduced speed of progression, shorter strides, prolonged double support phase) and muscular function (premature recruitment of gastrocnemius and late relaxation of tibialis anterior during stance phase) were identified regardless the severity of the clinical score. The gait analysis procedure was able to provide the clinician with evidence of motor abnormalities prior to functional disturbance observable by a trained physician. These minimal dysfunctions may have resulted from reflex mechanisms impaired by delayed transmission through long loop pathways or else as a result of a nonspecific protective gait strategy to improve balance control. The technique described in this study may be useful to identify earlier starting points for follow-up and physiotherapy.
Altered nerve growth factor level in the optic nerve of patients affected by multiple sclerosis
Authors: Micera Alessandra , Lambiase Alessandro , Rama Paolo , Aloe Luigi
Published: January 2007

In this study we measured with a highly sensitive two-site immunoenzymatic assay the levels of nerve growth factor (NGF) in human optic nerve affected by multiple sclerosis (MS). The result of this study showed an elevated increase of NGF in the MS optic nerves, as compared to the level of NGF found in the optic nerves non-affected by this demyelinating disorder. Moreover, the results showed that the optic nerves also expressed trkA NGF receptor and NGFmRNA, most likely by oligodendrocytes, implying that NGF is locally produced and suggesting that the presence of NGF might be regulated by an autocrine mechanism. These and other ongoing studies on animal models indicate that altered NGF levels are among one of the early symptoms of these demyelinating diseases. The physiopathological role of NGF in the optic nerve during demyelinating disorders remains however to be defined.
Treatment of progressive multiple sclerosis with pulse cyclophosphamidel methylprednisolone: Response to therapy is linked to the duration of progressive disease
Authors: Hohol Marika J , Olek Michael J , Orav E John , Stazzone Lynn , Hafler David A , Khoury Samia J , Dawson David M , Weiner Howard L
Published: January 2007

Objective: To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Scerosis (MS). Background: MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patient with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4-8 week intervals similar to lupus nephritis protocols. Design/Methods: We investigated a series of 95 consecutive progressive MS patient treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint associations were examined between outcome and patient characteristics including gender age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS. Result: Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patient that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients. Conclusions: Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patient enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agent for progressive MS, duration of progression should be considered as a randomization and analysis variable.
Evidence for the genetic role of human leukocyte antigens in low frequency DRBI*1501 multiple sclerosis patients in Israel
Authors: Karni A , Kohn Y , Saftirmnn C , Abraimsky O , Barcellos L , Oksenberg J R , Kahana E , Karussis D , Chapman J , Brautbur C
Published: January 2007

A strong association exist between m ultiple sclerosis (MS) and the DRB1 *1SO 1 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p2I has previously been observed in DRBI*1SO positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB 1*1SO1 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1SO effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRBS, DQAI and DQBI, BAT-2, MIB and D65248. Dta analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRBI * 1303 allele was significandy more frequent among the MS patiens There was a trend towards transmission disequilibrium of DRBS *1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRBI * 1303 observed in our family patient provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patiens Th us, DRBI * 1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRBS*1SO0 patient.
Long term use of Desmopressin for urinary symptoms in multiple sderosis
Authors: Tubridy N , Addison R , Schon F
Published: January 2007

The benefit of desmopressin (DDAVP) in the treatment of the urinary symptoms of multiple sclerosis has until now only been shown in short crossover studies of up to 6 weeks. We report 19 patient who have used the drug for an average of 2 years and 4 months, 18 of whom confirmed continued dramatic benefit without any obvious change in dosage used or efficacy and with few side effects. Ten of the 19 patienit had also used DDAVP during daytime for special occasions with notable success. This is the first study to suggest that DDAVP is safe and effective in long term use in MS.
Sexual dysfunction in multiple sderosis: II. Correlation analysis
Authors: Zivadinov R , Zorzon M , Bosco A , Bragadin L Monti , Moretti R , Bonfigli L , Iona L G , Cazzato G
Published: January 2007

Sexual dysfunction affect a large part of patient suffering from multiple sclerosis, but some aspect of i clinical presentation and aetiology are not clearly defined yet. In an unselected sample of 108 patient with definite multiple sclerosis we investigated the relationship between symptoms of sexual dysfunctioning and sphincteric dysfunction, patient' and disease characteristics, disability and neurological impairment psychological and cognitive functioning. Sexual dysfunction directly correlated with presence of physical disorders (r=0.37, P=0.0004) low educational level (r=0.32, P <0.002) disability (r=0.3 1, P <0.003) age at onset of symptoms (r=0.30, P <0.003) sphincteric dysfunction (r=0.30, P <0.003), age (r=0.30, P< 0.004) depression (r=0.29, P< 0.005) fatigue (r=0.29, P=0.005) cognitive deterioration (r=0.26, P< 0.0 1) primary-progressive co urse of disease (r=0.25, P < 0.02) ne urological impairment (r=0.25, P < 0.02), marriage (r0.24, P < 0.02) anxiety (r0.23, P < 0.03) male gender (r0.22, P=0.03) bladder dysfunction (r=0.29, P <0.04) and u nemployment (r0.2 1, P< 0.04). Sexual dysfunction correlated inversely with relapsing -remitting co urse of disease (r -0.31, P < 0.002). No correlation was fo und between sexual dysfunction and bowel dysfunction, duration of disease, secondary-progressive course of disease, number and frequency of sexual intercourses in the last year, number of partners, number of exacerbations in the last year, number of months since last exacerbation, masturbation, and fertility. In conldusion, the association between sexual dysfunction and sphincteric dysfunction indicates a common aetiology corresponding to the frequent involvement of the spinal cord in multiple sclerosis, but the concomitant correlation between sexual dysfunction and other variables suggest the possible aetiological role of physical psychological and sociological factors as well.
Negative impact of cardiac evaluation before vascular surgery
Authors: Krupski William C , Nehler Mark R , Whitehill Thomas A , Lawson Robert C , Strecker Pamela K , Hiatt William R
Published: January 2007

The optimal preoperative evaluation of cardiac risk in patients with peripheral vascular disease is controversial. In developing a paradigm for preoperative cardiac workup, potential adverse effects of evaluation and cardiac intervention must be considered. This study analyzed the deleterious outcomes of extensive, comprehensive cardiac evaluation and intervention before planned vascular surgery in patients treated at the Denver Department of Veterans Affairs Medical Center.

Over a 12-month period between 1994 and 1995, 161 patients were scheduled to undergo major vascular operations; 153 patients came to operation. The decision to pursue a cardiac evaluation was variously made by a combination of surgeons, cardiologists, and anesthesiologists. No defined protocol was followed. Cardiac history, chest X-rays and ECGs were obtained for all patients. Extendedcardiac evaluation included these studies plus special tests, including echocardiography (echo), radionuclide ventriculography (RNVG), dipyridamole thallium scintigraphy (DTS), and cardiac catheterization (CC). Extended cardiac evaluations were undertaken in 42 patients. Complications related to percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) were also recorded. Cardiac mortality and morbidity after vascular interventions were itemized in all 153 patients.

Forty-two male patients, aged 68 6 9 years, underwent extended cardiac evaluations before planned vascular operations. The median elapsed time for cardiac workup was 14 days (mean 30 6 59 days). The median and mean times from cardiac workup to vascular surgery were 25 days and 76 6 142 days, respectively. Eighteen (43%) patients had echo or RNVG; 22 (52%) patients had DTS; 27 (64%) had CC; 9 (21%) had PTCA; 7 (17%) had CABG. Sixteen (38%) patients had untoward events related to cardiac evaluation. Eight patients (19%: one with cerebrovascular disease, and seven with aortic aneurysms) refused vascular surgery after extended cardiac workup. Complications attributable to CC, PTCA, and CABG included prosthetic graft infection, pseudoaneurysms (two), sternal wound infections (two), renal failure and brain anoxia. Two patients with severe limb ischemia who were candidates for revascularization ultimately required amputations because of delay due to cardiac evaluations.

Extensive cardiac evaluation prior to vascular operations can result in morbidity, delays, and refusal to undergo vascular surgery. The underlying indication for vascular operations and the local iatrogenic cardiac complication rates must be considered before ordering special studies.
Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of HeartBar®
Authors: Maxwell Andrew J , Anderson Barbara E , Cooke John P
Published: January 2007

We investigated the clinical effects of a food bar enriched with l-arginine and a combination of other nutrients known to enhance the activity of endothelium-derived nitric oxide (EDNO) in individuals with claudication from atherosclerotic peripheral arterial disease. The study was a 2-week, double-blind, placebo-controlled trial of subjects randomized to three groups (two active bars, one active and one placebo bar, and two placebo bars per day) followed by an 8-week open-label period. Subjects (n = 41) were outpatient volunteers with intermittent claudication. Pain-free and total walking distances were measured by variable-grade, treadmill exercise testing. Quality of life was assessed using the Medical Outcome Survey (SF-36). After 2 weeks of treatment, the pain-free walking distance increased 66% while the total walking distance increased 23% in the group taking two active bars/day. The general and emotional/social functioning components of the SF-36 also improved. These effects were not observed in the one active bar/day and placebo groups. The effects were maintained after 10 weeks and, in addition, an improvement in walking distance was observed in the group taking one active bar. These findings reveal that use of a nutrient bar designed to enhance EDNO activity improves pain-free and total walking distance as well as quality of life in individuals with intermittent claudication.
Vascular endothelial growth factor is efficiently synthesized in spite of low transfection efficiency of pSG5VEGF plasmids in vascular smooth muscle cells
Authors: Dulak Jozef , Józkowicz Alicja , Ratajska Anna , Szuba Andrzej , Cooke John P , Dembińska-Kieć Aldona
Published: January 2007

The limitation of lipotransfection with plasmid vectors is its low efficiency and the short-term expression of introduced genes. This is particularly important when the synthesis of high amounts of therapeutic products is required. However, growth factors with paracrine action overcome this problem. The aim of our study was to check whether the amounts of vascular endothelial growth factor (VEGF) generated after plasmid lipotransfection into vascular smooth muscle cells (VSMC) can be sufficient to stimulate endothelial cell proliferation.

Two plasmids, pSG5-VEGF121 and pSG5-VEGF165, harboring human VEGF121 and VEGF165 iso-forms were constructed and lipotransfected into COS-7 cells or to rat VSMC. The transfection efficiency, estimated by the expression of control, b-galactosidase gene, was about 50% in COS- 7 but rarely exceeded 5% in VSMC. However, despite this, the smooth muscle cells generated high amounts of VEGF protein, up to 3 ng/ml medium. The biological activity of this VEGF was confirmed by enhanced proliferation of human umbilical vein and coronary artery endothelial cells, stimulated with conditioned media of pSG5-VEGF transfected cells. Thus, the low transfection efficiency does not preclude the generation of high amounts of VEGF by VSMC. After reaching the maximum at about 48 h after transfection, the generation of VEGF decreased in the following days. Such a situation may be sufficient for the gene therapy of restenosis when the long-term expression of therapeutic gene(s) is not necessary. Thus, we suggest that the pSG5-VEGF121 and pSG5-VEGF165 plasmids can be used for therapeutic application.
The endothelium: a new target for therapy
Authors: Cooke John P
Published: January 2007

At one time considered merely a monolayer of cells lining the vascular conduit, the endothelium has emerged recently as an organ with functions as complex as any in the body. A highly active regulatory organ, the endothelium senses and assesses the hemodynamic, humoral, and inflammatory signals to which it is constantly exposed by the blood and responds by secreting factors that affect vessel tone and structure. These interactions are not merely of academic interest. It has been increasingly recognized that endothelial dysfunction plays a pivotal role in the development and progression of atherosclerosis and coronary artery disease.
Short-term treatment with transdermal nicotine affects the function of canine saphenous veins
Authors: Clouse W Darrin , Rud Kevin S , Hurt Richard D , Miller Virginia M
Published: January 2007

Experiments were designed to determine the effects of nicotine treatment on the functions of saphenous veins used for coronary artery bypass grafts in dogs. Dogs received either no treatment or transdermal nicotine for 5 weeks at doses of 11 mg, 22 mg or 44 mg/day. Saphenous veins were removed and suspended for the measurement of isometric force in organ chambers. Endothelium was removed mechanically from some rings. NG-mono-methyl-l-arginine (l-NMMA; 10-4 M) was used to inhibit the production of nitric oxide. Contractions to alpha2-adrenergic stimulation were decreased in veins from dogs treated with a 22-mg/day dose of transdermal nicotine. In addition, endothelium-dependent relaxations to adenosinediphosphate (10-8-10-4 M) and the calcium ionophore A23,187 (10-8-10-6 M) were decreased in veins from dogs with a 22-mg/day dose and increased in veins from dogs treated with a 44-mg/day dose. These relaxations were inhibited by l-NMMA. Plasma concentrations of oxidized products of nitric oxide were decreased only in dogs treated with 22 mg/day of nicotine. The relaxation of rings without endothelium (direct response on the smooth muscle) to nitric oxide were not altered by nicotine treatment. These results suggest that the short-term treatment of dogs with intermediate (22 mg/day) but not low (11 mg/day) or high (44 mg/day) doses of transdermal nicotine decreases the endothelial function of veins used for coronary artery bypass grafts. Therefore, changes in plasma products of nitric oxide and endothelium-depen-dent relaxations mediated by nitric oxide are related to the dose of nicotine treatment.
Antisense and gene therapy to prevent restenosis
Authors: Ehsan Afshin , Mann Michael J
Published: January 2007

A primary pathologic response to vascular injury is the proliferation and migration of vascular smooth muscle cells and the development of neointimal lesions. An increasing body of knowledge regarding the molecular and genetic basis of neointimal disease has created a unique opportunity for the treatment of this complex disorder. Gene therapy attempts to correct pathobiological processes by either inhibiting or correcting cellular functions at the level of gene expression. These endpoints are achieved by the delivery of either functional genes or oligonucleotides, capable of interfering with a cell's programmed machinery. Since the early 1990s, the evolution of this technology, along with an ever-expanding source of pathobiological information, has led to many novel approaches for the treatment of restenosis in arterial balloon injury as well as vein graft bypass failure. Using a variety of targets, inhibition of proliferation has predominantly been achieved through direct disruption of the cell cycle machinery. In addition, others have demonstrated successful inhibition by interfering with the signals for cellular proliferation or the enhancement of anti-proliferative stimuli. As this exciting therapeutic alternative evolves, improvements in safety, specificity and efficiency will enhance the likelihood of widespread clinical application.
Evaluation of treatment efficacy of Raynaud phenomenon by digital blood pressure response to cooling
Authors: Maricq Hildegard R , Jennings J Richard , Valter Ivo , Frederick Margaret , Thompson Bruce , Smith Edwin A , Hill Robin ,   Raynaud's Treatment Study Investigators
Published: January 2007

Our previous studies have suggested that digital blood pressure response to cooling could provide a measure of the efficacy of treatments that are administered to patients with Raynaud phenomenon (RP). This method was used on 158 primary RP patients participating in a multicenter, randomized clinical trial that compared the efficacy of sustained-release nifedi-pine with temperature biofeedback in the treatment of RP. A pill placebo and electromyography served as controls. The response to local finger cooling was measured at 30°,20°,15° and 10°C in a temperature-controlled room under standardized conditions.

The results showed that, at the 15°C and 10°C local cooling temperatures, the patients in the nifedipine group had a higher mean digital systolic blood pressure, a higher relative digital systolic blood pressure (RDSP), a smaller proportion of subjects with RDSP, 70% and a smaller proportion of subjects with a zero reopening pressure than the patients in the three other treatment groups. These results were statistically significant at 10°C, the nifedipine group being significantly different from all others (p, 0.05); no significant difference was found between the three other treatment groups.
Spurious systolic hypertension in youth
Authors: O'Rourke Michael F , Vlachopoulos Charalambos , Graham Robert M
Published: January 2007

Six young men diagnosed with systolic hypertension had normal carotid pressure wave contours, normal synthesized aortic pressure wave contours and normal diastolic and mean pressures in upper limb arteries. Elevated brachial systolic pressure was caused by a high narrow systolic peak of the pressure wave. This was attributed to amplification of the pressure wave between the ascending aorta and upper limb (radial and brachial) arteries that is associated with attainment of full body length and very distensible arteries. These young men were not truly hypertensive. Exaggeration of the upper limb systolic peak represented an extreme of the normal pressure wave pattern in youth, where amplification is greater than in childhood or in older subjects. This phenomenon accounts for the rapid increase in systolic pressure between the ages of 5 and 20 years, and the relative plateau in systolic pressure between the ages of 20 and 45 years that is seen in population studies.
Differential expression of nitric oxide by dermal microvascular endothelial cells from patients with scleroderma
Authors: Romero Luz I , Zhang Dan-Ning , Cooke John P , Ho Hoai-Ky V , Avalos Esperanza , Herrera Rafael , Herron G Scott
Published: January 2007

Vascular abnormalities in scleroderma are fundamental to the pathogenesis of this disease. The objective of this study was to characterize dermal microvascular endothelial cells (DMEC) isolated from scleroderma patients with respect to growth and expression of the constitutive form of endothelial nitric oxide synthase (eNOS). DMEC from patients with both systemic sclerosis (SSc) and localized scleroderma (Loc Scl) contained small intact microvascular structures in contrast to single cell isolations obtained from control skin. Immunoaffinity selection on anti-PECAM-1 beads yielded pure populations of DMEC expressing normal markers. While the morphology and initial growth of SSc DMEC closely paralleled control cells, the growth of SSc DMEC decreased with time in culture (doubling time of 3 days vs. 5 days). Expression of ecNOS mRNA was reduced in both Loc Scl and SSc as shown by semi-quantitative RT-PCR (p, 0.001). Western blots showed variable but generally lower ecNOS protein levels and decreased levels of nitrogen oxides in media were found from both SSc and Loc Scl relative to control cells. The results indicate an intrinsic defect in the mechanism of nitric oxide production in DMEC isolated from scleroderma patients and suggest its possible involvement in the pathophysiology of scleroderma.
Successful anticoagulation with hirudin in a patient with mesenteric venous thrombosis and multiple coagulation abnormalities
Authors: Gordon Mary Beth , Beckman Joshua A
Published: January 2007

A case of multiple thrombotic diatheses discovered in the setting of mesenteric venous infarction is discussed. The patient had deficiencies of protein C, protein S, antithrombin III; was heterozygous for factor V Leiden; and had polycythemia vera. Adequate anticoagulation could not be established with heparin administration and hirudin was used. The diagnosis of mesenteric venous infarction, thrombotic tendency of multiple coagulation diatheses, and use of hirudin are discussed.
Predicting plaque rupture: enhancing diagnosis and clinical decision-making in coronary artery disease
Authors: Fischer Avi , Gutstein David E , Fayad Zahi A , Fuster Valentin
Published: January 2007

Atherosclerosis is the process underlying coronary artery disease, myocardial infarction and cerebrovascular disease and is a leading cause of morbidity and mortality in industrialized countries. The atherosclerotic plaque is often indolent and progressive and may destabilize without warning. Components of the atherosclerotic plaque, including structural, cellular and molecular characteristics, determine its vulnerability to rupture. The imaging techniques currently available utilize invasive and non-invasive methods to characterize coronary artery stenoses. Detection, however, usually occurs late in the course of disease after symptoms have presented. Much effort has recently been directed at early detection and in defining markers of atherosclerotic disease. Our challenge for the future is to find non-invasive imaging modalities that can predict plaque vulnerability before irreversible damage has occurred. Through early detection and a targeted treatment strategy we hope to reduce the burden of ischemic heart disease.
Protein kinase C activation and its pharmacological inhibition in vascular disease
Authors: Meier Matthias , King George L
Published: January 2007

Vascular complications in diabetes mellitus are known to be associated with the activation of the protein kinase C (PKC) pathway through the de novo synthesis of diacylglycerol (DAG) from glycolytic intermediates. Specific PKC isoforms, mainly the b- and d-isoforms, have been shown to be persistently activated in diabetic mellitus. Multiple studies have reported that the activation of PKC leads to increased production of extracellular matrix and cytokines, enhances contractility, permeability and vascular cell proliferation, induces the activation of cytosolic phospholipase A2 and inhibits the activity of Na+-K+-ATPase. These events are not only frequently observed in diabetes mellitus but are also involved in the actions of vasoactive agents or oxidative stress. Inhibition of PKC by two different kinds of PKC inhibitors - LY333531, a selective PKC-b-isoform inhibitor, and vitamin E, d-alpha-tocopheron - were able to prevent or reverse the various vascular dysfunctions in vitro and in vivo. Clinical studies using these compounds are now ongoing to evaluate the significance of DAG-PKC pathway activation in the development of vascular complications in diabetic patients.
Multiple skeletal muscle mitochondrial DNA deletions in patients with unilateral peripheral arterial disease
Authors: Brass Eric P , Wang Hong , Hiatt William R
Published: January 2007

Peripheral arterial disease (PAD) is associated with metabolic derangements and accumulation of the common 4977 bp mitochondrial DNA (mtDNA) deletion mutation. The current study was undertaken to test the hypothesis that PAD is associated with multiple mtDNA deletions. Gastrocnemius biopsies were obtained from nine patients with unilateral PAD. DNA extracted from the biopsies was analyzed for mtDNA deletions using a primer- shift PCR strategy. Multiple primers and strict, prospective criteria were used to identify deletions. PAD was associated with multiple mtDNA deletions (average of 8.2 distinct deletions in muscle from the hemodynamically affected limb). mtDNA injury was present in both the worse- and less-affected limbs of the unilateral PAD patients, and the estimated degree of mtDNA injury was strongly correlated in the two limbs on an intra-subject basis. The 4977 bp deletion was frequently identified, but was not always the deletion of highest frequency in individual samples. The estimated relative frequency of the 4977 bp deletion was correlated with the overall mtDNA injury in the biopsies. In summary, PAD is associated with mtDNA injury as reflected by multiple deletion mutations. As the mutations are not limited to the ischemic limb in unilateral patients, they are unlikely to contribute to the pathophysiology of claudication.
Hirudin therapy during thrombolysis for venous thrombosis in heparin-induced thrombocytopenia
Authors: Reilly Muredach P , Weiss Richard , Askenase Alan , Tuite Catherine , Soulen Michael , Mohler Emile R
Published: January 2007

Heparin-induced thrombocytopenia (HIT) is the most common drug-related thrombocytopenia. Thromboembolic complications occur in approximately 50% of patients with HIT and result in limb amputation and death in up to 20% and 30% respectively. Because patients with a history of HIT may require future intravenous anticoagulation but have a high-risk of thromboembolism if re-challenged with heparin, alternative therapies are necessary when further anticoagulation is indicated. The use of direct thrombin inhibitors in HIT patients who also require thrombolytic therapy offers unique challenges to anticoagulant monitoring and safety. We present a case of progressive ileofemoral deep venous thrombosis in a patient with a history of HIT in order to review the combined use of hirudin and thrombolysis in this setting.
Adenosine and chronic ischemia of the lower limbs
Authors: Pasini F Laghi , Capecchi PL , Di Perri T
Published: January 2007

Adenosine is an endogenous nucleoside with multiple biological properties which plays a central role in the pathophysiology of tissue ischemia. Adenosine signals an imbalance between oxygen demand and supply, and it initiates responses to redress such a discrepancy. Besides its vasodilating properties, adenosine possesses anti-platelet and anti-neutrophil activities and provides cytoprotection. Adenosine is presumably the main mediator of the preconditioning phenomenon. During ischemia of the lower limbs, adenosine plays a physiological role by inducing vasodilatation and by preventing microcirculatory failure. Exercise training prolongs claudication distance possibly by inducing pulse increases of adenosine and consequently skeletal muscle preconditioning. Moreover, the adenosine increase which follows the administration of some drugs, such as buflomedil and propionylcarnitine, opens new perspectives in the management of leg ischemia. In fact, the concept arises of an ischemic (exercise-dependent) or pharmacologic preconditioning in the treatment of patients with claudication.
Low molecular weight heparins for arterial thrombosis
Authors: Nenci Giuseppe G , Minciotti Alessandra
Published: January 2007

The use of low molecular weight heparin (LMWH) for the prevention and treatment of venous thromboembolism has been validated by numerous clinical trials and meta-analyses over the past 25 years. More recently, the possibility of extending treatment with LMWH to the arterial disease where thrombosis is a prominent feature has led to the planning of many clinical trials, several of which have been already published. LMWH has been tested in settings such as acute coronary syndromes, including myocardial infarction, surgery or percutaneous revascularization for coronary and peripheral arteries, and stroke. In most indications, LMWH has proved to be superior to or at least as effective as unfractionated heparin and it is also easier to administer.
Cost implications of low molecular weight heparins as prophylaxis following total hip and knee replacement
Authors: Bell Gregory K , Goldhaber Samuel Z
Published: January 2007

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are serious and costly complications of total hip and knee replacement surgery. The risk of these complications is significantly reduced by prophylaxis. Low molecular weight heparins (LMWH) are being used for this indication with increased frequency. The objective of this study was to assess the cost implications of LMWH for the prevention of symptomatic DVT and PE complications following total hip and knee replacement surgery. The study design was cost analysis based on utilization and the costs of medical resources for prophylaxis and treatment of DVT/PE. A retrospective hospital data set was used to assess symptomatic DVT/PE complication rates and medical resource utilization in patients receiving warfarin, other, and no prophylaxis. The results of a clinical trial were used to estimate relative reductions in risk of symptomatic DVT/PE due to prophylaxis with LMWH. The 7721 total hip and knee replacement patients analyzed were admitted in 1992 in 57 acute-care non-federal hospitals. The measurements were of incremental costs or charges expected to be saved as a result of using LMWH prophylaxis instead of warfarin prophylaxis. Prophylaxis using LMWH rather than warfarin reduces the expected total costs (charges) of treatment by $50 ($193), not including the pharmaceutical costs associated with prophylaxis. The cost reduction in favor of LMWH was sensitive to several factors, including blood monitoring costs and DVT/PE complication rates. Where a reduction of one day in hospital stay could be realized from LMWH's early onset of action, the cost (charges) reduction increased to $226 ($624). In conclusion, LMWH has the potential to offer several short- and long-term cost advantages compared with warfarin, mostly due to lower test costs associated with prophylaxis and reduced complication rates.
Altered gait profile in subjects with peripheral arterial disease
Authors: Gardner Andrew W , Forrester Larry , Smith Gerald V
Published: January 2007

The purpose of this study was to determine whether peripheral arterial disease (PAD) subjects had impaired temporal and spatial gait characteristics compared to non-PAD controls at preferred and rapid self-selected walking paces. A total of 28 PAD subjects with intermittent claudication (age = 71 -1; mean -SEM) and 15 non-PAD controls with at least one cardiovascular risk factor but no ambulatory leg pain (age = 71 -1) were recruited. Gait parameters consisting of velocity, cadence, stride length, swing time, stance time, single-support time, double-support time, and base of support were recorded at the preferred and rapid walking paces. At the rapid walking pace, velocity was 22% slower (p, 0.001) in the PAD subjects compared with the non-PAD controls (99.9 - 3.3 vs. 117.5 - 5.3 cm/s) due to an 8% (p = 0.019) slower cadence (99.9 - 1.7 vs. 103.3 - 2.4 steps/min) and a 14% (p, 0.001) shorter stride length (119.8 - 2.9 vs. 135.8 - 4.2 cm/stride). The PAD subjects spent 5% less of the gait cycle in the swing phase (p = 0.006) and 3% more in stance (p = 0.006) than their non-PAD counterparts. During the stance phase, the PAD subjects spent 5% less of the gait cycle in single-stance (p = 0.004) and 16% more in double-stance (p = 0.007). Similar results were obtained at the preferred walking pace. In conclusion, compared with the controls, PAD subjects adopted an ambulatory pattern that favored greater gait stability at the expense of greater walking speed at either their preferred or rapid self-selected paces.
Diameter, pressure and compliance relationships in dorsal hand veins
Authors: Shykoff Barbara E , Hawari Feras I , Izzo Joseph L
Published: January 2007

The diameter-pressure characteristics of dorsal hand veins previously have not been characterized. In this study, the effects of distending pressure with and without infused norepinephrine on diameter and compliance were observed. The elevation needed for venous collapse was measured, and the effects of baseline constriction on venous reactivity were assessed. In seven supine subjects, a brachial cuff on an elevated arm was used to generate distending pressures while a linear variable displacement transformer (LVDT) measured changes in venous diameter. Arctangent functions of distending pressure were fitted to the normalized diameter, then compliance functions were calculated. In supine subjects, 5-15 cm of elevation emptied dorsal hand veins. Norepinephrine decreased the venous diameter at any distending pressure by increasing the P50 without significantly changing the midpoint slope. Compliance was a nearly single-valued function of the normalized diameter with a maximum value at about 60% distention. Reactivity depends on distending pressure and baseline P50. Percentage constriction is a function of initial and final P50 and of distending pressure.
Heparin-induced thrombocytopenia: natural history, diagnosis, and management
Authors: Deitcher Steven R , Carman Teresa L
Published: January 2007

Heparin-induced thrombocytopenia (HIT) is an under-recognized, limb- and life-threatening complication of pharmacologic heparin administration. Antibody formation against heparin complexed to platelet factor 4 (PF4) is central to the pathogenesis of HIT. Heparin: PF4 antibodies promote platelet activation and aggregation as well as excess thrombin generation which may lead to clinical thrombosis. HIT should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. HIT is a clinical diagnosis. Specialized HIT assays should be interpreted with care. The cornerstone of HIT management is the discontinuation of all forms of heparin exposure and the institution of anticoagulation with an alternative agent. The direct thrombin inhibitors lepirudin and argatroban are currently available and approved for use in patients with HIT.
Effects of cilostazol on resting ankle pressures and exercise-induced ischemia in patients with intermittent claudication
Authors: Mohler Emile R , Beebe Hugh G , Salles-Cuhna Sergio , Zimet Richard , Zhang Peter , Heckman Jeffrey , Forbes William P
Published: January 2007

During exercise, patients with intermittent claudication (IC) have decreased limb arterial blood pressure that recovers during rest. A novel method for assessing dynamic recovery of function is measurement of the hemodynamic response after exercise. Cilostazol (Pletal®), a new agent for the treatment of IC, increases walking distance and may decrease ischemic burden. The objective of this study was to assess the effect of cilostazol versus placebo on hemodynamic measurements after exercise-induced ischemia in patients with IC.

Two double-blind, placebo-controlled studies with similar inclusion/exclusion criteria and duration (24 weeks) were pooled. Patients walked on a treadmill at 2.0 miles/h (3.2 km/h) on a 12.5% grade until the claudication-limited maximal walking distance (MWD) was reached. Anterior and posterior tibial pressures were measured with Doppler ultrasound at baseline and at 1, 5, and 9 min during recovery. Area under the curve (AUC), a measure of the time course of recovery of systolic pressure after exercise-induced ischemia, and ankle-brachial index (ABI) were calculated and compared using analysis of variance (ANOVA).

All three treatment groups (308 patients randomized to cilostazol 100 mg bid, 303 to cilostazol 50 mg bid, and 299 to placebo) had similar baseline characteristics. Mean post-exercise AUC for cilostazol 100 mg and 50 mg bid versus placebo increased by 0.31 ( p = 0.001) and 0.26 ( p= 0.004), respectively. Mean resting ABI increased by 0.03 ( p = 0.0039) and 0.04 ( p = 0.0001) in the cilostazol 100 mg and 50 mg bid groups, respectively.

In conclusion, following 24 weeks of treatment, cilostazol increased the ABI at rest and improved the recovery time of ankle pressures post-exercise.
Microcirculation in chronic venous insufficiency
Authors: Gschwandtner Michael E , Ehringer Herbert
Published: January 2007

In this review, the anatomy and physiology of the venous system and its pathophysiology are described. Theories regarding the possible causes of disturbances in venous microangiopathy are summarized. The theories concern the deoxygenation of red blood cells, arteriovenous shunts, fibrin cuffs, and the trapping of growth factors and/or white blood cells. Furthermore, microlymphatic, neurologic and hemorheologic disturbances in venous disease are outlined. Findings in venous microangiopathy obtained from histology, capillary microscopy, microlymphography, laser Doppler fluxmetry and transcutaneous oxygen partial pressure are detailed. Finally, the recently discovered pattern of perfusion in microcirculation within and around venous ulcers is discussed.
Ultrasound and thrombolysis
Authors: Francis Charles W , Suchkova Valentina N
Published: January 2007

Thrombolytic therapy and mechanical interventions are frequently used in the treatment of both arterial and venous thrombotic disease. Limitations to these approaches include failure to achieve reperfusion and complications including bleeding and vessel wall damage. Increasing evidence indicates that the use of ultrasound offers potential therapeutic advantages. This review considers two distinct approaches which include the use of high intensity ultra-sound to mechanically fragment clots and also the use of low intensity ultrasound to augment enzymatic fibrinolysis. High intensity ultrasound can be delivered via catheter or transcutaneously to disrupt clots in vitro or in animal models into small fragments. Initial clinical studies demonstrate potential clinical value in peripheral and coronary arterial thrombosis and occluded saphenous vein bypass grafts treated with the catheter approach. Studies in vitro indicate that low intensity ultrasound accelerates enzymatic thrombolysis through non-thermal mechanisms involving improvement in drug transport. The effect is larger at low frequencies, which also offer better tissue penetration and less heating. The ability to accelerate thrombolysis has been confirmed in animal models demonstrating markedly increased reperfusion and minimal toxicity. The use of ultrasound to mechanically disrupt occlusive thrombi or to accelerate enzymatic thrombolysis offers a new approach to treating occlusive thrombotic disease.
The relationship between history of falling and physical function in subjects with peripheral arterial disease
Authors: Gardner Andrew W , Montgomery Polly S
Published: January 2007

The purpose of this study was to determine whether peripheral arterial disease (PAD) subjects with a history of falling had more impaired physical function than their non-falling counterparts. A total of 120 PAD subjects (26%) who had fallen over the past year and 346 PAD subjects (74%) who had not fallen were evaluated. Additionally, subjects were characterized on physical function, consisting of balance, strength, ambulatory function, and monitored physical activity, as well as PAD-specific measures of ankle/brachial pressure index (ABPI) and treadmill claudication distances.

Full-tandem stance time was 19% shorter ( p ≤ 0.001) in the fallers than in the non-fallers (7.2 ± 0.3 vs 8.9 ± 0.1 s; mean ± SEM), and the self-reported ability to climb stairs was 36% lower (27 ± 4 vs 42 ± 2%). Furthermore, the fallers were 126% more likely ( p ≤ 0.001) to report ambulatory stumbling and unsteadiness, took 14% longer ( p = 0.022) to perform five sequential sit-to-stand transfers using an armless chair, covered 16% shorter distance ( p ≤ 0.001) during a 6-min walk test, and were 25% less physically active than the non-fallers. The groups had similar ABPI and treadmill claudication distances ( p ≤ 0.05). A history of falling was independently related to the self-reported ability to climb stairs, the full-tandem stance time, self-reported ambulatory stumbling and unsteadiness, and daily physical activity (multiple R = 0.47, p ≤ 0.001). In conclusion, impairments in multiple domains of physical function were associated with a history of falling in PAD subjects with intermittent claudication. Furthermore, the link between poor physical function and falling was independent of PAD severity.