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Background and Aims: The management of persistent type II endoleaks (T2E) is often problematic for the endovascular specialist, with a lack of clear evidence for the best approach for embolization. The aim of this study was to evaluate the safety and efficacy of translumbar embolization (TLE) for T2E following endovascular aneurysm repair (EVAR)., Methods: This retrospective review included 27 embolizations performed on 23 patients with a median age of 78 (range 67-94 years; male: female 15:9), during the period September 2006 to July 2018. Primary outcome was freedom from aneurysm sac growth defined as <2 mm sac diameter increase on subsequent computed tomography., Results: The initial technical success rate was 100%, with complete "on table" embolization of the T2E on fluoroscopy; however, 4 (15%) patients needed repeat TLE due to persistent endoleak identified on follow-up computed tomography or because of further sac expansion. Satisfactory stasis was achieved in these 4 cases following a second embolization. The mean volume of embolic injected was 7.4 mL per case. Feeding vessels were identified on angiography in all cases; the nidus was supplied by lumbar branches in 21 cases, by the inferior mesenteric artery in 1 case and by both in a further 5 cases. Freedom from aneurysm sac growth (defined as < 2 mm) following 1 or 2 separate TLE was achieved in 18 (78%) and 20 (86%) patients, respectively. The major complication rate was <5% with one case of psoas abscess presenting 7 months following embolization; there were 2 minor complications in the form of intraprocedural transient abdominal pain., Conclusion: The translumbar approach is a safe and effective technique to treat T2E, as evidenced by the low complication and reintervention rate.

Background: Abdominal aortic aneurysm (AAA) repair in patients with organ transplant remains a challenge. We looked at AAA repair in patients with organ transplants at our tertiary liver and kidney transplant unit., Methods: A retrospective analysis of a prospectively maintained database was undertaken from January 2008 to July 2018. We looked at patient demographics, type of repair, and technical success including reinterventions, perioperative transplant organ function, and 30-day and 1-year survival rate. Eight of 662 patients who underwent AAA repair had a solid organ transplant. Of these, 5 were kidney transplants, 2 liver transplants, and 1 had kidney and liver transplant; 75% were male; and average age was 63.4 (range: 49-83). All patients had asymptomatic AAAs, and 6 were treated with standard endovascular repair, 1 standard repair with iliac branch device, and 1 open repair. Adjunctive techniques such as CO 2 angiograms, deployment of main body through contralateral iliac, low-profile sheaths, custom-made stent grafts, and temporary axillo-femoral shunting were used to protect transplant organs. Thirty-day survival was 100% with 1 death at 5 months from liver failure, and 1 patient has a persistent type-2 endoleak 3 years after the procedure., Conclusion: Abdominal aortic aneurysm repair in patients with organ transplants can be undertaken using adjunctive endovascular and open surgical techniques.

Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS. Our data indicate that reduced ccf-mtDNA is a component of PMS, concluding that it may indeed be a hallmark of broader neurodegeneration., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Background: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue., Methods: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model., Results: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores., Conclusions: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Previous reports have suggested higher periprocedural complications after ipsilateral antegrade femoral arterial access (AA). We looked at a contemporary series comparing complication rates between AA and contralateral retrograde femoral arterial access (RA) for femoropopliteal angioplasty., Method: A prospective review of all cases between 2010 and 2015 in a United Kingdom tertiary vascular center. Demographical and procedural data were obtained for those undergoing percutaneous femoropopliteal angioplasty. The primary outcome looked at periprocedural complications including retroperitoneal hematoma, pseudoaneurysm, hematoma requiring transfusion, arteriovenous fistulation, and surgical intervention. Secondary outcomes included contrast and radiation doses in addition to procedural failure leading to major amputation., Results: A total of 556 (66% male) patients underwent femoropopliteal angioplasty, 461 (82%) via AA. Groups were of comparable age, sex, comorbidity, and symptomatology. AA patients had a lower body mass index, 26 versus 29 ( P = .005). No significant difference was seen in periprocedural (15.8% AA vs 11.6% RA; P = 0.292) or access site complications (3.7% AA vs 1.1% RA; P = 0.186). There was less need for a closure device, 40.3% AA vs 73% RA ( P < .01), less contrast, 94 mL AA: 114 mL RA ( P < .001), and less radiation, 3487 cGy cm 2 AA: 9697 cGy cm 2 RA ( P < .001). Arterial access was also associated with greater technical success of 83.8%: 73.3% RA ( P = .002)., Conclusions: Arterial access is associated with higher technical success and reduced contrast/radiation doses with no significant difference in complications compared to RA contrary to previous reports.

Importance: Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non-multiple sclerosis-related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)-related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease., Objective: To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG-positive and MOG-IgG-positive patients., Design, Setting, and Participants: Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England., Main Outcomes and Measures: The difference in seizure frequency between the AQP4-IgG-positive and MOG-IgG-positive patient groups was determined., Results: Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG-positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P < .008, Fisher test). On magnetic resonance imaging, all 5 MOG-IgG-positive patients had inflammatory cortical brain lesions associated with the seizures. In 3 of the 5 MOG-IgG-positive patients, seizures occurred as part of the index event. Four of the 5 presented with encephalopathy and seizures, and disease relapsed in all 5 patients. Four of these patients were receiving immunosuppressant medication at last follow-up, and 3 continued to take antiepileptic medication. In contrast, the only AQP4-IgG-positive patient with seizures had a diagnosis of complex partial epilepsy preceding the onset of NMO by several years and experienced no encephalitic illness; her magnetic resonance imaging results demonstrated no cortical, subcortical, or basal ganglia involvement., Conclusions and Relevance: Patients with MOG-IgG-associated disease were more likely to have seizures and encephalitis-like presentation than patients with AQP4-IgG-associated disease.

Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab., Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers., Results: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39-215) months and follow-up from time of first alemtuzumab cycle 20 (14-21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone., Conclusions: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.

Objective: Graft angioplasty combines the durability and ability of surgical bypasses to treat long arterial occlusions with the minimally invasive nature of endovascular procedures. The purpose of this study was to evaluate the efficacy of single and repeated graft angioplasty in revising failing infrainguinal vein bypass grafts and to determine predictors of medium- and long-term freedom from revision after graft angioplasty., Method: This was a retrospective analysis from a prospectively maintained database. Consecutive endovascular revisions of graft-threatening lesions identified by duplex ultrasound surveillance were reviewed from 2003 to 2010. Patients were followed up until death, major amputation, or the end of follow-up, with the data last updated on January 1, 2013., Results: 178 graft angioplasty procedures performed in 114 bypass grafts in 103 limbs from 98 patients were studied. At 5 years, freedom from revision was 22.6%, graft survival was 45.8%, amputation-free survival was 57.9%, and patient survival was 64.9%. Analysis of repeated angioplasties found no evidence that effectiveness diminishes significantly with the number of previous angioplasties performed (p=.892). Higher Rutherford Grade of ischemia and longer time interval from index surgery to first angioplasty were significant positive predictors of medium- and long-term patency., Conclusion: Percutaneous transluminal angioplasty of infrainguinal vein grafts is safe and effective in the treatment of failing grafts identified by duplex surveillance. Graft angioplasties do not lose effectiveness when repeated and have shown cumulative benefit in prolonging graft survival. Treatment of claudicants and time interval from graft implantation of more than 6 months at the time of first angioplasty are positive predictors of at least medium-term patency after graft angioplasty., (Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Introduction: The aim of this study was to assess the durability of superficial femoral artery (SFA) stents and factors that affect stent patency., Methods: A retrospective assessment of 214 SFA stent procedures between 2003 and 2012 was conducted from a prospectively compiled database. Patency rates and patient outcomes were compiled from case notes and computerized records. Stent patency was confirmed by either duplex scan or clinical examination (palpable distal pulse). Survival and patency were compared across a range of factors using Kaplan-Meier plots and log-rank tests. Factors found to be significant were further assessed by Cox regression models., Results: Data were analyzed for 214 limbs in 205 patients. Inclusion criteria included those patients who received an SFA stent for treatment of claudication or critical limb ischemia (CLI) with follow-up data. This gave a study group of 151 limbs divided into 76 claudicant and 75 patients with CLI (male-female ratio = 103:48, mean age 71 years, standard deviation 11.7). Seventy-one percent of procedures were elective and 29% were emergency procedures; 53% of procedures were carried out on a day case basis. Median follow-up was 11 months (range 1 day-89 months). Patency was significantly worse for patients with CLI (P = .009), with a 1- and 3-year patency of 63% and 34% compared to 79% and 60% in patients with claudication. Significant factors associated with patency included oral therapy controlled diabetes (P = .003), lesions located in either the mid-SFA (P = .029) or the mid-popliteal (P = .013), and periprocedural complications (P = .005). There was no significant difference in patency rates between insulin-dependent and nondiabetic patients (hazard ratio: 1.0, 95% confidence interval: 0.4-5.6, P = .983). The overall amputation rate for the total study group was 5%. Patients with 1- and 3-year survival were 98% and 96% in the claudication group and 74% and 51%, respectively, in the CLI group., Conclusion: SFA stents have superior outcomes in claudicants. Patency is related to severity of disease, diabetes, and location of disease., (© The Author(s) 2015.)

The Loeys-Dietz syndrome is a multisystem connective tissue disorder characterized by aortopathy, arterial tortuosity, peripheral aneurysms, and skeletal features. The peripheral arteriopathy is an important cause of morbidity and potential mortality. This report presents 2 cases: the first demonstrating a 5-cm pseudoaneurysm of the right internal mammary artery and the second demonstrating a 2.3-cm aneurysm of the left internal mammary artery, each following aortic root surgery. These were successfully treated with percutaneous techniques. No complications were seen at follow-up as long as 2 years. Patients with Loeys-Dietzs syndrome require comprehensive long-term vascular follow-up and are likely to require percutaneous vascular interventions., (Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.)

Background: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada., Methods: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective., Findings: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2])., Interpretation: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible., Funding: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Establishing a diagnosis of giant cell arteritis, or indeed ruling it out, may be difficult. We describe an evaluation of temporal artery colour duplex ultrasound as first line investigation in patients with suspected giant cell arteritis., Methods: A retrospective cohort study of all patients undergoing colour duplex ultrasound for suspected giant cell arteritis between January 2005 and January 2014 was undertaken at a teaching hospital. A minimum clinical follow-up of three months was required. Patients were classified on the basis of ultrasound reports, using described features such as a halo sign or arterial wall thickening and clinical diagnosis of giant cell arteritis after at least 3 months follow-up, determined by the treating physician. The relationship of colour duplex ultrasound to a final clinical diagnosis of giant cell arteritis was analysed., Results: A total of 87 patients underwent colour duplex ultrasound: 36 (41%) had clinically confirmed giant cell arteritis at 3-month follow-up. The positive predictive value of colour duplex ultrasound for a clinical diagnosis at 3 months was 97% (95% confidence interval (CI) 93 to 99%) and negative predictive value 88% (95% CI 76 to 95%). Sensitivity was 81% (95% CI 64 to 92%) and specificity 98% (95% CI 90 to 100%)., Conclusions: A high positive and negative predictive value of arteritis on colour duplex ultrasound indicates that temporal artery biopsy may be unnecessary in suspected giant cell arteritis, particularly where clinical suspicion of giant cell arteritis is high or low.

Background: The fixed, progressive disability associated with late Multiple Sclerosis (MS) is known to have a major impact on patients and their families, but the impact of relapse earlier in the disease course is less well documented, particularly from the patient׳s perspective. This study aimed to understand the effects of relapse for people with MS (PwMS), focussing on the years immediately after starting disease modifying therapy (DMT) when experience of a relapse may particularly influence a patient׳s opinions of their disease and its therapy., Methods: This was a multi-centre, retrospective, observational research study, recruiting patients from 7 UK NHS Hospital Trusts. Consenting patients with relapsing-remitting MS (RRMS), who had started a DMT more than 36 months before screening, were sent a study questionnaire. Data on MS relapses and treatments over 3 years were collected simultaneously from medical records., Results: One hundred and three patients completed the questionnaires. Relapses were under-reported to health care professionals, with 28% of respondents failing to report their most recent attack and 46% declaring they had failed to report an attack in the past. During their most recent relapse, 67% of those in paid employment reported taking time off sick, 48% reduced working hours temporarily, and 41% worked reduced hours and took time off sick. Sixty-six percent required additional support to undertake routine daily tasks during their most recent relapse. A range of effects of relapse which cannot be measured in financial terms were also reported, including effects on physical abilities, mental health and family roles and relationships., Conclusion: This contemporary UK-based study provides an insight into the experience of relapse early in the treatment of RRMS from the patient perspective. The comparison of documented patient reported relapses reveals some deficiencies in the recording of relapses which is important to address in view of the reported impact of individual relapses, and emphasises relapse reduction as a worthy treatment aim., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: In 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the short term but recognised that reducing disability over the longer term might dramatically improve the cost effectiveness. The UK Risk-sharing Scheme (RSS) was established to ensure cost-effective provision by prospectively collecting disability-related data from UK-treated patients with MS and comparing findings to a natural history (untreated) cohort. However, deficiencies were found in the originally selected untreated cohort and the resulting analytical approach. This study aims to identify a more suitable natural history cohort and to develop a robust analytical approach using the new cohort., Design: The Scientific Advisory Group, recommended the British Columbia Multiple Sclerosis (BCMS) database, Canada, as providing a more suitable natural history comparator cohort. Transition probabilities were derived and different Markov models (discrete and continuous) with and without baseline covariates were applied., Setting: MS clinics in Canada and the UK., Participants: From the BCMS database, 898 'untreated' patients with MS considered eligible for drug treatment based on the UK's Association of British Neurologists criteria., Outcome Measure: The predicted Expanded Disability Status Scale (EDSS) score was collected and assessed for goodness of fit when compared with actual outcome., Results: The BCMS untreated cohort contributed 7335 EDSS scores over a median 6.4 years (6357 EDSS 'transitions' recorded at consecutive visits) during the period 1980-1995. A continuous Markov model with 'onset age' as a binary covariate was deemed the most suitable model for future RSS analysis., Conclusions: A new untreated MS cohort from British Columbia has been selected and will be modelled using a continuous Markov model with onset age as a baseline covariate. This approach will now be applied to the treated UK RSS MS cohort for future price adjustment calculations.

Vein graft stenosis is a well-recognized complication of infrainguinal bypass surgery. Balloon angioplasty is an accepted method for managing vein graft stenosis in selected patients. This intervention is not without complication. We present 2 cases of delayed pseudoaneurysm formation after balloon angioplasty of vein graft stenoses. Both cases showed a persistent contrast stain or blush as an indication of vein wall damage and propose that this is a radiological harbinger of delayed rupture and pseudoaneurysm formation.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Objective: To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT)., Methods: Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system-autoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses., Results: Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses., Interpretation: Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT., (Copyright © 2013 American Neurological Association.)

Increasing options are dictating the development of new algorithms to provide guidance in the treatment of people with multiple sclerosis (MS). There is a wealth of evidence on the safety and efficacy of interferon-beta and glatiramer acetate, which have been used in Europe and in the United States for more than 10 years. The spectrum of approved indications for these conventional disease modifying therapies includes the treatment of relapsing-remitting MS, secondary progressive MS, and the clinically isolated syndrome. Beyond these therapies we already have the recently introduced antibody natalizumab and, in some countries, the immunosuppressive agent mitoxantrone. Oral therapies are expected in the near future, with the sphingosin-1-phosphate receptor modulator fingolimod approved in the US and the EU and the purine nucleoside analogue cladribine in Australia and Russia. The evidence on all of these conventional and novel therapeutics is reviewed in this paper to provide an overview of the changing landscape of MS treatment.

Aim: Occlusion or severe stenosis of pedal and plantar arteries limits surgical options for critical limb ischaemia (CLI). Below-the-ankle (BTA) angioplasty is potentially useful as an adjunct to proximal angioplasty. In this study, the feasibility and outcome of this procedure were explored, as they have not been evaluated previously., Methods: Patients' demographics, indications, procedures and outcomes were recorded. Outcomes were determined by technical success, primary patency, limb salvage and amputation-free survival (AFS) rates., Results: Between 2004 and 2008, 42 cases of BTA angioplasty were performed for 39 patients. Forty cases (95.2%) had CLI. Technical success was achieved in 88% of cases. At 6, 12 and 24 months, AFS was 70.7%, 60.9% and 57.1%, limb salvage was 84.9%, 81.9% and 81.9% and patient survival was 83.3%, 73.8% and 67.3, respectively. Seven major amputations (16.6%) were performed, four of which had failed angioplasty. Two patients required re-intervention. Univariate analysis showed insulin-dependent diabetics, occlusive lesions, failure of angioplasty and state of the run off to be the predictors of limb loss., Conclusions: BTA angioplasty for pedal and plantar arterial occlusive disease is technically feasible. It has good medium-term clinical outcome and limb salvage in a group of patients with poor surgical options., (Copyright (c) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-alpha are largely produced by memory B cells. These results point to an in vivo switch in the cytokine "program" of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.

There has been longstanding interest in how B-cell responses may contribute to the pathology of neurological diseases. Traditionally, the premise has been that any such contribution relates to the potential of B cells to produce autopathogenic antibodies. Targeting autoantibodies continues to be an important therapeutic approach, particularly in disorders where the role of antibodies is relatively well established, such as in certain inflammatory disorders of peripheral nerves or the neuromuscular junction. In other conditions, such as multiple sclerosis, the role of circulating antibodies targeting the CNS has been less clear, although pathologic studies continue to implicate CNS-reactive antibodies, as well as B cells within the CNS compartment. Recently, new insights into fundamental properties of B cells have suggested that these cells may contribute in an antibody-independent fashion, both to normal immune responses, and in the context of immune mediated diseases. Here, we will consider the potential roles of antibody-dependent as well as antibody-independent B-cell involvement in multiple sclerosis. The topic is of particular interest at a time that B-cell-directed therapies are being evaluated for this and other autoimmune diseases.

B-cells may be involved at many levels in the pathogenesis of MS, starting from the earliest stage of antigen capture, continuing through the processes of tissue damage and even extending through to remyelination and repair. Recent advances in our understanding of normal B-cell biology and abnormal regulation of their functions in relation to the pathology of MS are discussed in this review. Current treatments already target B-cell responses; consequently, this effect may be one explanation for the efficacy of these treatments in some types of MS. The results of specific anti-B-cell therapies are awaited. Even if success is limited, it is possible that targeting this important group of cells, whether as antigen-presenting cells, as regulators of immune responses or as antibody-secreting cells, will form at least part of more successful treatment strategies in the future.

Glatiramer acetate (GA) therapy of patients with multiple sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T cells is consistently observed and associated with clinical benefit in a human autoimmune disease. We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 cytokine network of monocytes in vivo. We further show that Th1- or Th2-polarized GA-reactive T cells isolated from untreated or treated MS patients mediate type 1 and 2 APC differentiation of human monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T cells, respectively. These observations are extended to human microglia, providing the first demonstration of type 2 differentiation of CNS-derived APCs. Finally, we confirm that the fundamental capacity of polarized T cells to reciprocally modulate APC function is not restricted to GA-reactive T cells, thereby defining a novel and dynamic positive feedback loop between human T cell and APC responses. In the context of MS, we propose that GA therapy results in the generation of type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients. In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic immune modulation.

Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.

Multiple sclerosis (MS) has a wide spectrum of clinical courses, characterized by multifocal central nervous system (CNS) damage, postulated to be mediated by CNS antigen-specific T cells. Dendritic cells (DC), the most potent antigen-presenting cell, play a pivotal role in the decision between T-cell activation or anergy. Monoclonal antibodies to CD1a (immature DC) and CD83 (mature DC) were used to screen lesions with evidence of recent demyelinating activity and chronic plaque and normal appearing white matter (NAWM) tissue sections from 12 MS cases by immunocytochemistry. No CD1a-positive cells were detected in the MS or control CNS tissue blocks investigated. CD83-positive cells were not detected in tissues from any of the control cases or in the majority of perivascular cuffs in the MS tissue sections. However; in eight of the MS tissue blocks with evidence of recent demyelination, and in one block each from chronic plaque and NAWM, small numbers of distinct CD83-positive cells were present within occasional perivascular cuffs. In one area only of MS NAWM were CD83-positive cells detected in the tissue parenchyma, in an area of intense immunological activity. DC in MS tissue may originate in the peripheral circulation as monocytes or immature DC and migrate to areas of plaque in response to signals received from CNS-produced chemokines.

Traditionally, emphasis has been placed on the roles of Th cells in generating and amplifying both cellular and humoral memory responses. Little is known about the potential contributions of B cell subsets to immunological memory. Resting memory B cells have generally been regarded as poor APC, attributed in part to the relative paucity of costimulatory molecules identified on their surface. We describe a novel subpopulation of human memory B cells that express CD80 in their resting state, are poised to secrete particularly large amounts of class switched Igs, and can efficiently present Ag to and activate T cells. This functionally distinct B cell subset may represent an important mechanism by which quiescent human B cells can initiate and propagate rapid and vigorous immune memory responses. Finally, these studies extend recent observations in the murine system and highlight the phenotypic and functional diversity that exists within the human B cell memory compartment.

Background: To determine if uncontrolled hypercholesterolaemia predisposes to progression of carotid artery stenosis., Methods: Fasting blood samples were collected from 76 patients referred for carotid duplex ultrasound for investigation of transient ischaemic attacks or recent stroke. Patients were grouped depending on the severity of the stenosis found. Patients on lipid lowering agents were excluded. The data were analysed using one way analysis of variance and the c2 test as appropriate., Results: There were more men in the 70-99% group (15 vs 6, c2 = 10.6, p < 0.001, Table I). The total cholesterol was raised in all three groups. Patients with carotid stenosis of 70-99% had significantly elevated triglycerides (2.4 mmol vs 1.47 mmol and 1.37 mmol, p < 0.003), low HDL (1.14 mmol vs 1.45 mmol and 1.18 mmol, p < 0.003) and a higher cholesterol/HDL ratio (5.56 vs 4.29 and 4.71, p < 0.014) compared with the other two groups. There was no difference in lipoprotein(a) in the three groups., Conclusions: Increased triglycerides and low HDL cholesterol seen in the 70-99% group suggest that a worsening lipid profile is associated with progression of carotid artery stenosis.

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.

It has been postulated that the efficacy of interferon-beta1a in multiple sclerosis may be due to the induction of type 2 cytokines. In this report we demonstrate that after 3 months of therapy, there is no sustained alteration in the plasma levels of type 1 (IL-12, IL-1beta and TNF-alpha) or type 2 (IL-6, IL-10) cytokines, but rather repeated induction of both with each injection. Little alteration is seen in the profile of cytokines induced with time, despite a decline in side effects. This suggests that IFN-beta1a causes repeated transient modulation of cytokine expression, but no sustained deviation in the type 1/type 2 balance.

The protective properties of knife-resistant armour are quantified by the distance a test blade penetrates beyond a test sample into clay at a given energy. At present there are two proposed standards: penetration to 5 mm and penetration to 20 mm. Armour made to the higher standard specification (5mm) is necessarily heavier as it offers more protection. To determine the safety of these standards a retrospective review of 71 consecutive computerised tomographic (CT) scans was made. The minimum distance from the skin to the vital organs was measured. No organ would have been breached at 5 mm of knife penetration deep to body armour. 41% of pleurae, 61% of livers, 64% of femoral arteries, 25% of spleens and 6% of hearts would have been breached at a depth of 20 m of knife penetration. There was no significant difference in the minimum skin to organ distances between male and female subjects. The 20 mm standard does not offer adequate protection against knife attacks.

Rhabdomyolysis as a result of major trauma is a well recognized cause of acute renal failure. Non-traumatic rhabdomyolysis causing transient renal impairment may occur following generalized convulsions. We present a case in which rhabdomyolysis following epilepsy was first indicated at urography by a delayed and increasingly dense persistent nephrogram.

Pre- and post-operative assessments are presented in 17 adult patients who have been treated with craniovertebral decompression for hindbrain herniation, 11 of whom had syringomyelia. Objective improvement in the size of the syrinx was seen in all 11 cases; contrary to expectation the hindbrain more frequently moved downwards than upwards after decompression of the tonsils and creation of an artificial cisterna magna. A method is reported for the quantitative assessment of hindbrain migration using magnetic resonance imaging (MRI). The degree of 'slump', further downward displacement of the hindbrain, was compared with the clinical outcome and the MRI appearances. Slump was more common than expected, although the severity was not usually great enough to produce symptoms. Slump was less marked where the artificial cisterna magna was generous (p less than 0.02). This quantitative method may be useful in assessing patients with unexplained post-operative symptoms and in comparing different surgical techniques.