Real-world persistence of multiple sclerosis disease-modifying therapies.

BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.

Correlates and trajectories of relapses in relapsing-remitting multiple sclerosis.

BACKGROUND AND AIMS: In people with relapsing-remitting multiple sclerosis (pwRRMS), data from studies on non-pharmacological factors which may influence relapse risk, other than age, are inconsistent. There is a reduced risk of relapses with increasing age, but little is known about other trajectories in real-world MS care. METHODS: We studied longitudinal questionnaire data from 3885 pwRRMS, covering smoking, comorbidities, disease-modifying therapy (DMT), and patient-reported outcome measures, as well as relapses during the past year. We undertook Rasch analysis, group-based trajectory modelling, and multilevel negative binomial regression. RESULTS: The regression cohort of 6285 data sets from pwRRMS over time showed that being a current smoker was associated with 43.9% greater relapse risk; having 3 or more comorbidities increased risk and increasing age reduced risk. Those diagnosed within the last 2 years showed two distinct trajectories, both reducing in relapse frequency but 25.8% started with a higher rate and took 4 years to reduce to the rate of the second group. In the cohort with at least three data points completed, there were three groups: 73.7% followed a low stable relapse rate, 21.6% started from a higher rate and decreased, and 4.7% had an increasing then decreasing pattern. These different trajectory groups showed significant differences in fatigue, neuropathic pain, disability, health status, quality of life, self-efficacy, and DMT use. CONCLUSIONS: These results provide additional evidence for supporting pwRRMS to stop smoking and underline the importance of timely DMT decisions and treatment initiation soon after diagnosis with RRMS.

Measuring disability in multiple sclerosis: the WHODAS 2.0.

INTRODUCTION: Reliable measurement of disability in multiple sclerosis (MS) using a comprehensive, patient self-reported scale, such as the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, would be of clinical and research benefit. METHODS: In the Trajectories of Outcome in Neurological Conditions-MS study, WHODAS 2.0 (WHODAS-36 items for working, WHODAS-32 items if not working, WHODAS-12 items short-form) was examined using Rasch analysis in 5809 people with MS. RESULTS: The 36- and 32-item parallel forms, and the cognitive and physical domains, showed reliability consistent with individual or group use. The 12-item short-form is valid for group use only. Interval level measurement for parametric statistics can be derived from all three scales which showed medium to strong effect sizes for discrimination across characteristics such as age, subtype, and disease duration. Smallest detectable difference for each scale was < 6 on the standardised metric of 0-100 so < 6% of the total range. There was no substantial differential item functioning (DIF) by age, gender, education, working full/part-time, or disease duration; the finding of no DIF for time or sample supports the use of WHODAS 2.0 for longitudinal studies, with the 36- and 32-item versions and the physical and cognitive domains valid for individual patient follow-up. CONCLUSIONS: Disability in MS can be comprehensively measured at interval level by the WHODAS 2.0, and validly monitored over time. Routine use of this self-reported measure in clinical and research practice would give valuable information on the trajectories of disability of individuals and groups.

Measuring coping in multiple sclerosis: The Coping Index-MS.

BACKGROUND: Coping in multiple sclerosis (MS) refers to cognitive and behavioural efforts to manage stresses imposed by the illness. Existing generic and disease-specific coping scales do not meet modern guidelines for scale development and cannot produce interval-level metrics to allow for change scores. OBJECTIVE: The main aim of this study was to develop a brief patient-reported outcome measure for coping in MS, capable of interval-level measurement. METHODS: Qualitative work in 43 people with MS leads to a draft scale which was administered to 5747 participants, with longitudinal collection in 2290. A calibration sample of 1000 subjects split into development and validation sets was used to generate three scales consistent with Rasch model expectations. RESULTS: The total Coping Index-MS (CI-MS-T), CI-MS-Internal (CI-MS-I) and CI-MS-External (CI-MS-E) cover total, internal and externally focused coping. All three scales are capable of interval-level measurement. Trajectory analysis of 9000 questionnaires showed two trajectories in CI-MS-T: Group 1 showed a low level of coping with slight decline over 40 months, while Group 2 had a better and stable level of coping due to improving CI-MS-I which compensated for the deteriorating CI-MS-E over time. CI-MS-T < 30 identified group membership at baseline. CONCLUSION: The CI-MS-T, CI-MS-I and CI-MS-E, comprising 20 items, provide interval-level measurement and are free-for-use in not-for-profit settings.

Quantifying the administration and monitoring time burden of several disease-modifying therapies for relapsing multiple sclerosis in the United Kingdom: A time and motion study.

BACKGROUND: The treatment landscape for relapsing multiple sclerosis (MS) has changed dramatically in recent decades, including an increasing number of high-efficacy disease-modifying therapies (DMTs) with varied administration and monitoring requirements. Coupled with greater focus on earlier treatment, these factors have resulted in stretching of the capacity of MS specialist services and allied healthcare professionals (HCPs). To assist with the effective planning of MS services in the UK NHS, this study quantified the administration and monitoring time burden associated with high-efficacy DMTs (alemtuzumab, cladribine tablets, fingolimod, natalizumab, and ocrelizumab) for relapsing MS. METHODS: A Time and Motion (T&M) study was conducted across four MS centres in the UK, over 3-4 months per centre (Aug 2019-Feb 2021). Time dedicated by HCPs (including but not limited to neurologists, MS specialist nurses, infusion nurses, and healthcare assistants) to pre-specified drug administration and monitoring activities, elicited during pre-study interviews at each centre, was assessed for each of the selected DMTs. Administration activities included: installing peripheral access; pre-medication administration (if needed); preparing drug for infusion; infusion initiation, monitoring, and disconnection; and patient monitoring post-infusion. Monitoring activities included: booking appointments for blood draws; blood draw; retrieval and review of blood results; maintaining blood records and follow-up with the patient; checking availability of MRI results and follow-up with the patient; booking appointments for neurologist or nurse consultations; and checking patient files prior to clinic visits. A T&M model was built using observational T&M study results, data obtained through pre-study interviews, as well as stipulated monitoring intervals from relevant Summaries of Product Characteristics for the selected DMTs, to estimate active HCP time with each DMT, extrapolated over a period of 4 years per-patient. RESULTS: For oral DMTs, projected total active HCP time (monitoring only) per-patient over 4 years was 14.7 h for cladribine tablets and 19.2 h for fingolimod. For infused DMTs, total time (administration and monitoring) for alemtuzumab was 37.7 h (6.0 and 31.6 h, respectively), 48.1 h for natalizumab (17.4 and 30.8 h, respectively), and 23.5 h for ocrelizumab (6.1 and 17.4 h, respectively). CONCLUSIONS: While active HCP time varied across centres, infused DMTs were projected to require the greatest amount of HCP time associated with administration and monitoring over 4 years versus oral DMTs. These findings may assist MS-specific HCPs in planning and delivering the equitable provision of DMT services for patients with relapsing MS.

Prevalence, treatment and correlates of depression in multiple sclerosis.

BACKGROUND: The prevalence of depression in Multiple Sclerosis (MS) is often assessed by administering patient reported outcome measures (PROMs) examining depressive symptomatology to population cohorts; a recent review summarised 12 such studies, eight of which used the Hospital Anxiety and Depression Scale-Depression (HADS-D). In clinical practice, depression is diagnosed by an individual structured clinical interview; diagnosis often leads to treatment options including antidepressant medication. It follows that an MS population will include those whose current depressive symptoms meet threshold for depression diagnosis, plus those who previously met diagnostic criteria for depression and have been treated such that depressive symptoms have improved below that threshold. We examined a large MS population to establish a multi-attribute estimate of depression, taking into account probable depression on HADS-D, as well as anti-depressant medication use and co-morbidity data reporting current treatment for depression. We then studied associations with demographic and health status measures and the trajectories of depressive symptoms over time. METHODS: Participants were recruited into the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study, with demographic and disease data from clinical records, PROMs collected at intervals of at least 9 months, as well as co-morbidities and medication. Interval level conversions of PROM data followed Rasch analysis. Logistic regression examined associations of demographic characteristics and symptoms with depression. Finally, a group-based trajectory model was applied to those with depression. RESULTS: Baseline data in 5633 participants showed the prevalence of depression to be 25.3 % (CI: 24.2-26.5). There were significant differences in prevalence by MS subtype: relapsing 23.2 % (CI: 21.8- 24.5), primary progressive 25.8 % (CI: 22.5-29.3), secondary progressive 31.5 % (CI: 29.0-34.0); disability: EDSS 0-4 19.2 % (CI: 17.8-20.6), EDSS ≥4.5 31.9 % (CI: 30.2-33.6); and age: 42-57 years 27.7 % (CI: 26.0-29.3), above or below this range 23.1 % (CI: 21.6-24.7). Fatigue, disability, self-efficacy and self esteem correlated with depression with a large effect size (>0.8) whereas sleep, spasticity pain, vision and bladder had an effect size >0.5. The logistic regression model (N = 4938) correctly classified 80 % with 93 % specificity: risk of depression was increased with disability, fatigue, anxiety, more comorbidities or current smoking. Higher self-efficacy or self esteem and marriage reduced depression. Trajectory analysis of depressive symptoms over 40 months in those with depression (N = 1096) showed three groups: 19.1 % with low symptoms, 49.2 % with greater symptoms between the threshold of possible and probable depression, and 31.7 % with high depressive symptoms. 29.9 % (CI: 27.6-32.3) of depressed subjects were untreated, conversely of those treated, 26.1 % still had a symptom level consistent with a probable case (CI: 23.5-28.9). CONCLUSION: A multi-attribute estimate of depression in MS is essential because using only screening questionnaires, diagnoses or antidepressant medication all under-estimate the true prevalence. Depression affects 25.3 % of those with MS, almost half of those with depression were either untreated or still had symptoms indicating probable depression despite treatment. Services for depression in MS must be pro-active and flexible, recognising the heterogeneity of outcomes and reaching out to those with ongoing symptoms.

Brain reserve and physical disability in secondary progressive multiple sclerosis.

Background: The brain reserve hypothesis posits that larger maximal lifetime brain growth (MLBG) may confer protection against physical disability in multiple sclerosis (MS). Larger MLBG as a proxy for brain reserve, has been associated with reduced progression of physical disability in patients with early MS; however, it is unknown whether this association remains once in the secondary progressive phase of MS (SPMS). Our aim was to assess whether larger MLBG is associated with decreased physical disability progression in SPMS. Methods: We conducted a post hoc analysis of participants in the MS-Secondary Progressive Multi-Arm Randomisation Trial (NCT01910259), a multicentre randomised placebo-controlled trial of the neuroprotective potential of three agents in SPMS. Physical disability was measured by Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and 25-foot timed walk test (T25FW) at baseline, 48 and 96 weeks. MLBG was estimated by baseline intracranial volume (ICV). Multivariable time-varying Cox regression models were used to investigate the association between MLBG and physical disability progression. Results: 383 participants (mean age 54.5 years, 298 female) were followed up over 96 weeks. Median baseline EDSS was 6.0 (range 4.0-6.5). Adjusted for covariates, larger MLBG was associated with a reduced risk of EDSS progression (HR 0.84,95% CI:0.72 to 0.99;p=0.04). MLBG was not independently associated with time to progression as measured by 9HPT or T25FW. Conclusion: Larger MLBG is independently associated with physical disability progression over 96 weeks as measured by EDSS in SPMS. This suggests that MLBG as a proxy for brain reserve may continue to confer protection against disability when in the secondary progression phase of MS. Trail registration number: NCT01910259.

Evaluating the effectiveness of simvastatin in slowing the progression of disability in secondary progressive multiple sclerosis (MS-STAT2): protocol for a multicentre, randomised controlled, double-blind, phase 3 clinical trial in the UK.

INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

CSF lymphocytic pleocytosis does not predict a less favourable long-term prognosis in MS.

OBJECTIVE: The role of CSF lymphocytic pleocytosis in predicting the clinical outcome of multiple sclerosis is unclear. We explored the impact of CSF pleocytosis at diagnosis on long-term disease progression in a large UK cohort. METHODS: We extracted demographic, clinical and CSF data of people with MS attending the MS clinics between 1996 and 2014 at two MS centres from the English Midlands. We compared EDSS at onset, follow up EDSS and progression indices Multiple Sclerosis Severity Score (MSSS), annualized change in EDSS and transition to secondary progression in the presence/absence of pleocytosis. Two-tailed student t-test, Mann-Whitney U test, Chi-Square or Fisher's exact tests were used for detecting the differences. RESULTS: A total of 247 patients with MS (178 females; mean age 42.4; 217 with relapsing onset) were followed up for an average of 13.56 years (median 12 years). Almost 18% had lymphocytic CSF ≥ 5 per microliter. CSF pleocytosis was not associated with higher EDSS at the time of LP or at follow up, and other progression indices like MSSS, annualized change in EDSS or transition to secondary progression. DISCUSSION: CSF pleocytosis at MS diagnosis does not predict higher long-term disability and has no long-term prognostic value in routine clinical circumstances. Differences between MS populations and potential differences in disease activity at the time of CSF analysis may account for differences between studies.

Case report: Unusual patient with dermatomyositis associated with SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a major challenge for clinicians. SARS-CoV-2 infection results in coronavirus disease 2019 (COVID-19), and it is best known for its respiratory symptoms. It can also result in several extrapulmonary manifestations such as neurological complications potentially experienced during the course of COVID-19. The association of dermatomyositis (DM) with COVID-19 pathogenesis has not been well-studied. This study aimed to present a previously healthy 37-year-old man, a soldier by profession, with symptoms of DM on the 4th day from the onset of COVID-19. The patient presented DM symptoms with both skin and muscle manifestations. The patient suffered from cough, fever, and fatigue to begin with, and reverse-transcription polymerase chain reaction (RT-PCR) reported positive for SARS-CoV-2 infection. The laboratory findings showed, intra alia, elevated muscle enzymes CK 8253 U/l (N: <145 U/l), a positive test for myositis-specific autoantibodies (anti-Mi-2), electrodiagnostic tests exhibited features of myopathy, with the presence of muscle and skin symptoms. The patient improved with corticosteroids and immunosuppressive agent therapy. In summary, the association between COVID-19 and the development of multi-system autoimmune disorders such as DM remains unclear. Nevertheless, viral infections such as SARS-CoV-2 may likely serve as a trigger.

Multiple Sclerosis vision questionnaire (MSVQ-7): Reliability, validity, precision and discrimination.

BACKGROUND: Visual dysfunction is common in people with Multiple Sclerosis (pwMS), associated with a variety of visual symptoms. Capturing the patient experience of these complex patterns of visual pathology is challenging. A valid and reliable patient reported measure, capable of detecting clinically significant change, would have considerable research and clinical benefits. We examined the properties of the MS Vision Questionnaire (MSVQ-7) in a large MS population. METHODS: Data were collected from participants in the UK-wide Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study: MS subtype and Expanded Disability Status Scale (EDSS) band from the clinical team, as well as serial packs including the MSVQ-7 and questionnaires on depression, anxiety and stigma. A calibration sample of 1000 pwMS contributing several years of follow-up were split into training and validation samples for a Confirmatory Factor Analysis and Rasch analysis. The Minimal Detectable Change (MDC) was computed as well as the Minimal Clinically Important Change (MIC), by an anchor-based method, for different MS subtypes. RESULTS: The MSVQ-7 is unidimensional and can be fit to the Rasch model with a solution discarding 3% of variance. Providing all 7 items are answered, the total can be converted to an interval-level metric for calculation of change scores and other parametric analyses. The % of missing values did not exceed 1.7%. Among 5478 pwMS, 80% reported visual problems. MSVQ-7 scores were categorised as mild for 36.1%, moderate for 33.6% and severe for 10.3%, and varied by MS subtype. In the follow-up sample of 2227 pwMS, 42.5% changed MSVQ-7 category between baseline and first follow-up (mean 22.6 months). The MIC exceeded the MDC so clinically significant change exceeds measurement error. While MDC was identical for relapsing and progressive MS, MIC varied by MS subtype, with smaller MIC in relapsing MS. Over one-quarter of the follow-up sample reported a clinically significant change in MSVQ-7: 12.2% improved and 13.5% deteriorated. For pwMS recruited within 2 years of diagnosis, 17.3% reported significant change on follow-up, all improving. MSVQ-7 scores showed strong associations with anxiety, depression and stigma (effect sizes>0.8). Duration, EDSS band and MS subtype all had effect sizes 0.2-0.49. A multinomial logistic regression exploring vision disturbance and depression, adjusted for age, gender, MS subtype, duration and disability, showed vision is the strongest significant predictor of depression. Each unit increase in interval MSVQ-7 increases risk by 10% of 'possible' and by 17% of 'probable' depression. CONCLUSIONS: The MSVQ-7 is a brief self-report measure of visual problems for pwMS. It can easily be converted to interval-level measurement for change scores or power calculations and has good precision and discrimination. Visual problems were reported by 80% of pwMS and changed over time, evidencing the need for regular monitoring. MIC varied by MS subtype, indicating that perception of impact changes over the disease course. Visual dysfunction significantly affects depression risk and perceived stigma, highlighting the importance of routine assessment of visual problems in comprehensive care. The MSVQ-7 has strong psychometric properties for adoption as a measure for vision in clinical and research settings.

The four self-efficacy trajectories among people with multiple sclerosis: Clinical associations and implications.

BACKGROUND: Longitudinal studies among people with Multiple Sclerosis (pwMS) have shown that self-efficacy is linked to physical, cognitive and psychological functioning. OBJECTIVES: To determine the distribution of self-efficacy in a large sample of pwMS, examining whether there are distinct groups which show different self-efficacy trajectories over time, and the health status characteristics of any groups identified. METHODS: Participants completed serial questionnaire packs, including Unidimensional Self-efficacy-MS (USE-MS) scale, for the Trajectories of Outcome in Neurological Conditions-MS (TONiC-MS) study over an average 46-month period. The resulting longitudinal data were analysed by a group-based trajectory model. RESULTS: 5887 pwMS were studied: mean age 50.2 years (SD 12.0); 73.6% female; Relapsing Remitting MS (61.8%), Secondary Progressive (22.9%), Primary Progressive (11.1%), Rapidly Evolving Relapsing Remitting MS (4.2%). Four distinct self-efficacy trajectories emerged, with declining, slightly declining, stable or improving self-efficacy, each showing different patterns of health status indicators such as EQ-5D-5L, disability and depression. USE-MS ≤ 18 at baseline detected all participants in the two declining groups. CONCLUSION: Future trials on interventions for self-efficacy should assume a priori that those with low levels of self-efficacy (USE-MS ≤ 18 at baseline) are likely to be on a declining trajectory and may need different interventions from those with stable self-efficacy.

Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy.

BACKGROUND AND OBJECTIVE: Quality of life in multiple sclerosis (MS) reflects complex relationships between symptoms (fatigue, spasticity pain, and bladder or vision dysfunction), disability, health perceptions, and self-efficacy. METHODS: In this cross-sectional study, a self-report questionnaire pack of patient reported outcome measures was collected from 5695 people with MS (pwMS) alongside clinical data from their neurologists. Each patient reported outcome measure was converted to interval-scaled estimates following fit to the Rasch model. The patient reported outcome measures, as well as perceived health, age, disease subtype and gender, were then subject to path analysis to analyse their relationships with quality of life (QoL), guided by the Wilson and Clearly conceptual framework. RESULTS: The final model explains 81.2% of the variance of QoL. Fatigue is clearly dominant, suggesting a means to intervene and improve QoL. The next most influential factors were disability and self-efficacy, which have similar effect levels. The model can be replicated for pwMS on disease modifying therapy and is largely invariant for gender and disease subtype. Age had an insignificant effect. CONCLUSIONS: In order to promote better QoL, MS care should include management of fatigue, interventions to ameliorate disability, and support to enhance self-efficacy. The range of skills needed for these treatments will require input from medical, nursing, therapy and psychology staff, so these findings provide evidence substantiating the need for pwMS to be provided with care by comprehensive multidisciplinary teams.

Differentiating vascular parkinsonism from idiopathic Parkinson's disease: a systematic review.

Vascular parkinsonism (VP) remains a loose constellation of various clinical features. We systematically reviewed studies comparing clinical, neuroimaging and other investigations that might distinguish VP from idiopathic Parkinson's disease (PD). Medline, Embase, Cinahl (R), and PsycINFO were searched by querying appropriate key words. Reports were included if the study population contained comparative findings between patients with VP and PD. Twenty-five articles fulfilled the selection criteria. Patients with VP were older, with a shorter duration of illness, presented with symmetrical gait difficulties, were less responsive to levodopa, and were more prone to postural instability, falls, and dementia. Pyramidal signs, pseudobulbar palsy, and incontinence were more common in VP. Tremor was not a main feature of VP. Structural neuroimaging was more likely to be abnormal in VP (90-100% of cases) than in PD (12-43% of cases), but there was no specific abnormal structural imaging pattern for VP. Two studies of presynaptic striatal dopamine transporters (using single photon emission computed tomography) showed a significant reduction in striatal uptake ratios in PD but not in VP, whereas another study found that only the mean asymmetry index was significantly lower in VP. Various other investigations, including alternative imaging techniques, electrophysiological, and neuropsychological studies, are reported, but the diverse diagnostic criteria used makes it difficult to reach any firm conclusions. The development of accepted international diagnostic criteria for VP is urgently needed to facilitate further studies.

Interactions of cubilin with megalin and the product of the amnionless gene (AMN): effect on its stability.

Cubilin, a 456 kDa multipurpose receptor lacking in both transmembrane and cytoplasmic domains is expressed in the apical BBMs (brush border membranes) of polarized epithelia. Cubilin interacts with two transmembrane proteins, AMN, a 45-50 kDa protein product of the amnionless gene, and megalin, a 600 kDa giant endocytic receptor. In vitro, three fragments of cubilin, the 113-residue N-terminus and CUB domains 12-17 and 22-27, demonstrated Ca2+-dependent binding to megalin. Immunoprecipitation and immunoblotting studies using detergent extracts of rat kidney BBMs revealed that cubilin interacts with both megalin and AMN. Ligand (intrinsic factor-cobalamin)-affinity chromatography showed that in renal BBMs, functional cubilin exists as a complex with both AMN and megalin. Cubilin and AMN levels were reduced by 80% and 55-60% respectively in total membranes and BBMs obtained from kidney of megalin antibody-producing rabbits. Immunohistochemical analysis and turnover studies for cubilin in megalin or AMN gene-silenced opossum kidney cells showed a significant reduction (85-90%) in cubilin staining and a 2-fold decrease in its half-life. Taken together, these results indicate that three distinct regions of cubilin bind to megalin and its interactions with both megalin and AMN are essential for its intracellular stability.

Changes in the chemical composition of surfactant-like particles secreted by rat small intestine in response to different dietary fats.

Consumption of dietary oil, viz., corn, fish, coconut, or olive, induced the secretion of surfactant-like particles (SLP) in rat intestine. These lipoprotein particles differ in (i) levels of alkaline phosphatase activity, (ii) lipid composition, and (iii) FA composition in response to feeding of different oils. The secreted particles had similar buoyancy (1.07-1.08 g/mL) and cholesterol/phospholipid molar ratios (0.61-0.72) except that feeding coconut oil to rats produced SLP with a low (0.18) cholesterol/phospholipid molar ratio compared to control animals. It is concluded from these observations that feeding different oils induces the secretion of lipoprotein particles in rat intestine with different chemical compositions.