Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study.

OBJECTIVES: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients. METHODS: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years. RESULTS: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (ß)=0.97), higher EDSS (ß=0.41), higher cord lesion number (ß=0.41), lower normalised cortical volume (ß=-0.15) and lower cord area (ß=-0.28) (C-index=0.81). Older age (ß=0.86), higher EDSS (ß=1.40) and cord lesion number (ß=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (ß=1.49), cord lesion number (ß=1.02) and lower normalised cortical volume (ß=-0.56) (C-index=0.88). Baseline age (ß=0.30), higher EDSS (ß=2.03), higher cord lesion number (ß=0.66) and lower cord area (ß=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (ß=1.87) and cord lesion number (ß=0.54) predicted EDSS=6.0 (C-index=0.91). CONCLUSIONS: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

Patients' views and experiences on the supported self-management/patient-initiated follow up pathway for breast cancer.

PURPOSE: To explore patients' expectations and experience of Supportive Self-Management (SSM)/ Patient Initiated Follow Up (PIFU) following breast cancer treatments over a 12-month period. METHODS: In total, 32/110 (29%) patient participants in the PRAGMATIC (Patients' experiences of a suppoRted self-manAGeMent pAThway In breast Cancer) study were interviewed at baseline, 3, 6, 9 and 12 months. Interviews in this sub-study used a mix-methods approach to explore understanding of the pathway, confidence in self-management, triggers to seek help and/or re-engage with the clinical breast team and impact of the COVID-19 pandemic. Responses to pre-assigned categories were summarised as counts/ percentages and collated in tabular or graphic format. Free responses were recorded verbatim and reviewed using framework analysis. RESULTS: Participants regarded the SSM/PIFU pathway as a way to save time and money for them and the National Health Service (NHS) (14/32; 44%) and as a means of assuming responsibility for their own follow-up (18/32; 56%). Most maintained (very/somewhat) confidence in managing their BC follow-up care (baseline 31/32, 97%; 12 months 29/31, 93%). During the year, 19% (5/26) stopped endocrine therapy altogether because of side effects. Qualitative analysis revealed general satisfaction with SSM/PIFU and described the breast care nurses as reassuring and empathic. However, there was a lingering anxiety about identifying signs and symptoms correctly, particularly for those with screen-detected cancers. There was also uncertainty about who to contact for psychological support. The COVID-19 pandemic discouraged some participants from contacting the helpline as they did not want to overburden the NHS. CONCLUSIONS: The results show that during the first year on the SSM/PIFU pathway, most patients felt confident managing their own care. Clinical teams should benefit from understanding patients' expectations and experiences and potentially modify the service for men with BC and/or those with screen-detected breast cancers.

Talking about Risk, UncertaintieS of Testing IN Genetics (TRUSTING): development and evaluation of an educational programme for healthcare professionals about BRCA1 & BRCA2 testing.

BACKGROUND: Mainstreaming of germline testing demands that all healthcare professionals have good communication skills, but few have genetic testing and counselling experience. We developed and evaluated educational workshops-Talking about Risk & UncertaintieS of Testing IN Genetics (TRUSTING). Contents included: presentations and exercises, an interview with a geneticist about BRCA testing, screening and prevention implications, filmed interactions between surgeons, a genetic counsellor and geneticists with a fictitious family (proband had a BRCA2 pathogenic variant with triple-negative breast cancer, her older sister-BRCA2 heterozygous, and cousin-negative for BRCA2 variant). METHODS: Twenty-one surgeons, 5 oncologists, 18 nurses and 9 genetic counsellors participated. Knowledge (18 item MCQ), communication skills (responses to 6 questions from proband and relatives) and self-confidence (discussing 9 genetic testing issues) were assessed pre- and post workshop. RESULTS: Knowledge scores improved significantly post workshop (mean change = 7.06; 95% confidence interval (CI) 6.37-7.74; P < 0.001), as did communication (mean change = 5.38; 95% CI 4.37-6.38; P < 0.001) and self-confidence (P < 0.001). DISCUSSION: Healthcare professionals' knowledge and self-confidence when discussing the risks and uncertainties in genetics are often poor. TRUSTING workshops significantly enhanced attendees' navigation of communication difficulties encountered and will be rolled out more widely.

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis.

BACKGROUND: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. OBJECTIVE: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. METHODS: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). RESULTS: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4-C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3-C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3-C6 correlated with concomitant and 1-year disability (r = -0.40/-0.62, p < 0.05, corrected). CONCLUSIONS: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Brain and cord imaging features in neuromyelitis optica spectrum disorders.

OBJECTIVES: To validate imaging features able to discriminate neuromyelitis optica spectrum disorders from multiple sclerosis with conventional magnetic resonance imaging (MRI). METHODS: In this cross-sectional study, brain and spinal cord scans were evaluated from 116 neuromyelitis optica spectrum disorder patients (98 seropositive and 18 seronegative) in chronic disease phase and 65 age-, sex-, and disease duration-matched multiple sclerosis patients. To identify independent predictors of neuromyelitis optica diagnosis, after assessing the prevalence of typical/atypical findings, the original cohort was 2:1 randomized in a training sample (where a multivariate logistic regression analysis was run) and a validation sample (where the performance of the selected variables was tested and validated). RESULTS: Typical brain lesions occurred in 50.9% of neuromyelitis optica patients (18.1% brainstem periventricular/periaqueductal, 32.7% periependymal along lateral ventricles, 3.4% large hemispheric, 6.0% diencephalic, 4.3% corticospinal tract), 72.2% had spinal cord lesions (46.3% long transverse myelitis, 36.1% short transverse myelitis), 37.1% satisfied 2010 McDonald criteria, and none had cortical lesions. Fulfillment of at least 2 of 5 of absence of juxtacortical/cortical lesions, absence of periventricular lesions, absence of Dawson fingers, presence of long transverse myelitis, and presence of periependymal lesions along lateral ventricles discriminated neuromyelitis optica patients in both training (sensitivity = 0.92, 95% confidence interval [CI] = 0.84-0.97; specificity = 0.91, 95% CI = 0.78-0.97) and validation samples (sensitivity = 0.82, 95% CI = 0.66-0.92; specificity = 0.91, 95% CI = 0.71-0.99). MRI findings and criteria performance were similar irrespective of serostatus. INTERPRETATION: Although up to 50% of neuromyelitis optica patients have no typical lesions and a relatively high percentage of them satisfy multiple sclerosis criteria, several easily applicable imaging features can help to distinguish neuromyelitis optica from multiple sclerosis. ANN NEUROL 2019;85:371-384.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

The zebrafish reference genome sequence and its relationship to the human genome.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Patients' and partners' views of care and treatment provided for metastatic castrate-resistant prostate cancer in the UK.

OBJECTIVE: Documentations of the experiences of patients with advanced prostate cancer and their partners are sparse. Views of care and treatment received for metastatic castrate-resistant prostate cancer (mCRPC) are presented here. METHODS: Structured interviews conducted within 14 days of a systemic therapy for mCRPC starting and 3 months later explored the following: treatment decisions, information provision, perceived benefits and harms of treatment, and effects of these on patients' and partners' lives. RESULTS: Thirty-seven patients and 33 partners recruited from UK cancer centres participated. The majority of patients (46%) reported pain was their worst symptom and many wanted to discuss its management (baseline-50%; 3 months-33%). Patients and partners believed treatment would delay progression (>75%), improve wellbeing (33%), alleviate pain (≈12%) and extend life (15% patients, 36% partners). At 3 months, most men (42%) said fatigue was the worst treatment-related side effect (SE), 27% experienced unexpected SEs and 54% needed help with SEs. Most patients received SE information (85% written; 75% verbally); many additionally searched the Internet (33% patients; 55% partners). Only 54% of patients said nurse support was accessible. CONCLUSION: Pain and other symptom management are not optimal. Increased specialist nurse provision and earlier palliative care links are needed. Dedicated clinics may be justified.

Enhancing decision-making about adjuvant chemotherapy in early breast cancer following EndoPredict testing.

OBJECTIVE: Chemotherapy side-effects can be substantial. There is increasing recognition that some oestrogen receptor positive (ER +ve), human epidermal growth factor receptor 2 negative (HER2 -ve) patients with breast cancer derive no benefit from chemotherapy and experience only iatrogenic harm. Gene expression profiling tests help refine recurrence risk and likely chemotherapy benefit. EndoPredict® is one such test, which classifies risks of distant recurrence as low or high in patients treated with surgery and adjuvant endocrine therapy alone. We compared treatment decisions pre-test and post-test results, patients' anxiety, decisional conflict, and oncologists' confidence about the decisions made. METHODS: Fourteen oncologists in 7 UK hospitals saw 149 pts judged to have equivocal indications for chemotherapy. Provisional treatment decisions were recorded then reconsidered when EPClin results were available. Pre-test and post-test results, patients completed State/Trait Anxiety Inventories (STAI), and the decisional conflict scale. Oncologists also recorded basic clinical details, their agreement with, and confidence about treatment decisions. RESULTS: Sixty-seven percent patients initially prescribed endocrine alone with high risk result upgraded to endocrine+chemotherapy (E + C); 83% prescribed E + C and had low risk scores, downgraded to E. None of 46 patients initially favouring E alone, who were low risk, changed decisions. Oncologists' confidence about decisions was significantly increased following the results (P = 0.002). Patients with downgraded treatment decisions had significantly lower anxiety scores (P = 0.045); those upgraded had increased scores (P = 0.001). Overall decisional conflict and uncertainty fell significantly post-test (P < 0.022). CONCLUSIONS: EndoPredict scores increased oncologists' and patients' decision-making confidence, generally improving the matching of risk with therapy decisions.

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease.

IMPORTANCE: Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. OBJECTIVE: This multicentre study tested previously reported criteria of '(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson's finger-type lesion' in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. DESIGN: Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. PARTICIPANTS: 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. RESULTS: MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. CONCLUSIONS: This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show that hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting that gross morphometric hippocampal plasticity occurs faster than previously thought.

Patient-reported outcome measures for cancer caregivers: a systematic review.

PURPOSE: Informal caregivers provide invaluable help and support to people with cancer. As treatments extend survival and the potential burdens on carers increase, there is a need to assess the impact of the role. This systematic review identified instruments that measure the impact of caregiving, evaluated their psychometric performance specifically in cancer and appraised the content. METHODS: A two-stage search strategy was employed to: (1) identify instruments that measure the impact of caregiving, and (2) run individual searches on each measure to identify publications evaluating psychometric performance in the target population. Searches were conducted in MEDLINE, EMBASE, CINAHL and PsycINFO and restricted to English for instrument used and article language. Psychometric performance was evaluated for content and construct validity, internal consistency, test-retest reliability, precision, responsiveness and acceptability. Individual scale items were extracted and systematically categorised into conceptual domains. RESULTS: Ten papers were included reporting on the psychometric properties of eight measures. Although construct validity and internal consistency were most frequently evaluated, no study comprehensively evaluated all relevant properties. Few studies met our inclusion criteria so it was not possible to consider the psychometric performance of the measures across a group of studies. Content analysis resulted in 16 domains with 5 overarching themes: lifestyle disruption; well-being; health of the caregiver; managing the situation and relationships. CONCLUSIONS: Few measures of caregiver impact have been subject to psychometric evaluation in cancer caregivers. Those that have do not capture well changes in roles and responsibilities within the family and career, indicating the need for a new instrument.

Structural imaging of the cervical spinal cord with suppressed CSF signal using DANTE pulse trains.

PURPOSE: We propose DANTE (Delays Alternating with Nutation for Tailored Excitation) moving fluid attenuation preparation pulse trains, in conjunction with T1 , T2 , and proton-density-weighted fast spin-echo (T1w-TSE, T2w-TSE and PDw-TSE) imaging readout, and three-dimensional fast low flip angle shots (3D-FLASH) T1 -weighted imaging readout to achieve CSF-suppressed high-spatial resolution multicontrast cervical spinal cord images. METHODS: DANTE pulse trains, consisting of a rapid series of low flip angle radiofrequency pulses interspersed with gradients, were used to substantially attenuate the longitudinal magnetization of flowing spins relative to static tissue/fluid, whose longitudinal magnetization is mostly preserved. We hypothesized that the contrast between spinal cord and cerebrospinal fluid (CSF) could be maximized due to moving CSF signal suppression. RESULTS: We demonstrate that metrics of contrast-to-noise ratio between spinal cord, nerve root, and CSF regions (CNRcord-CSF and CNRnerve-CSF ) are improved by at least a factor of 2 when compared with images acquired with non-prepared approaches and with 2D multiple-echo data image combination (MEDIC) imaging. In addition, we find that sagittal image quality can be significantly improved due to flow suppression effects from the DANTE preparation pluses. CONCLUSION: DANTE prepared imaging techniques for moving CSF signal attenuation are promising tools for cervical spinal cord imaging.

MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction. OBJECTIVE: The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON. METHODS: A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed. RESULTS: All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3). CONCLUSIONS: A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON.

Low myo-inositol indicating astrocytic damage in a case series of neuromyelitis optica.

Astrocytic necrosis is a prominent pathological feature of neuromyelitis optica (NMO) lesions and is clinically relevant. We report 5 NMO-related cases, all with longitudinally extensive lesions in the upper cervical cord, who underwent cervical cord (1) H-magnetic resonance spectroscopy. Lower myo-inositol/creatine values, suggesting astrocytic damage, were consistently found within the NMO lesions when compared with healthy controls and patients with multiple sclerosis (MS), who showed at least 1 demyelinating lesion at the same cord level. Therefore, the in vivo quantification of myo-inositol may distinguish NMO from MS. This is an important step toward developing imaging markers for clinical trials in NMO.

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride.

Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.

One component? Two components? Three? The effect of including a nonexchanging "free" water component in multicomponent driven equilibrium single pulse observation of T1 and T2.

Quantitative myelin content imaging provides novel and pertinent information related to underlying pathogenetic mechanisms of myelin-related disease or disorders arising from aberrant connectivity. Multicomponent driven equilibrium single pulse observation of T1 and T2 is a time-efficient multicomponent relaxation analysis technique that provides estimates of the myelin water fraction, a surrogate measure of myelin volume. Unfortunately, multicomponent driven equilibrium single pulse observation of T1 and T2 relies on a two water-pool model (myelin-associated water and intra/extracellular water), which is inadequate within partial volume voxels, i.e., containing brain tissue and ventricle or meninges, resulting in myelin water fraction underestimation. To address this, a third, nonexchanging "free-water" component was introduced to the multicomponent driven equilibrium single pulse observation of T1 and T2 model. Numerical simulations and experimental in vivo data show that the model to perform advantageously within partial volume regions while providing robust and reproducible results. It is concluded that this model is preferable for future studies and analysis.

Brain atrophy and lesion load predict long term disability in multiple sclerosis.

OBJECTIVE: To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). DESIGN: From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1-2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing-remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0-3.5, n=111) or moderately impaired (EDSS=4-6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. RESULTS: In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R(2)=0.74 in the whole group and R(2)=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R(2)=0.68), lesion volumes in moderately impaired relapse onset patients (R(2)=0.21) and whole brain atrophy in primary progressive MS (R(2)=0.34). CONCLUSIONS: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.

Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma.

Atopic or immunoglobulin E (IgE)-mediated diseases include the common disorders of asthma, atopic dermatitis and allergic rhinitis. Chromosome 13q14 shows consistent linkage to atopy and the total serum IgE concentration. We previously identified association between total serum IgE levels and a novel 13q14 microsatellite (USAT24G1; ref. 7) and have now localized the underlying quantitative-trait locus (QTL) in a comprehensive single-nucleotide polymorphism (SNP) map. We found replicated association to IgE levels that was attributed to several alleles in a single gene, PHF11. We also found association with these variants to severe clinical asthma. The gene product (PHF11) contains two PHD zinc fingers and probably regulates transcription. Distinctive splice variants were expressed in immune tissues and cells.