Search

Experimental allergic neuritis was induced in 30 rabbits with extract of bovine peripheral nerve in complete Freund's adjuvant. Of the 22 animals that completed the study, nine animals were plasmapheresed within two weeks of inoculation and 13 animals served as controls. The plasmapheresed animals developed a less severe form of EAN than the controls. Differences were apparent in clinical weakness, weight loss, degree of dispersion of the muscle action potential and histological changes. [ABSTRACT FROM AUTHOR]

Background: Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia., Methods: We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration., Results: In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds., Conclusion: Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

A substantial proportion of the adult United States population with type 2 diabetes (T2D) are undiagnosed, calling into question the comprehensiveness of current screening practices, which primarily rely on age, family history, and body mass index (BMI). We hypothesized that a polygenic score (PGS) may serve as a complementary tool to identify high-risk individuals. The T2D polygenic score maintained predictive utility after adjusting for family history and combining genetics with family history led to even more improved disease risk prediction. We observed that the PGS was meaningfully related to age of onset with implications for screening practices: there was a linear and statistically significant relationship between the PGS and T2D onset (-1.3 years per standard deviation of the PGS). Evaluation of U.S. Preventive Task Force and a simplified version of American Diabetes Association screening guidelines showed that addition of a screening criterion for those above the 90th percentile of the PGS provided a small increase the sensitivity of the screening algorithm. Among T2D-negative individuals, the T2D PGS was associated with prediabetes, where each standard deviation increase of the PGS was associated with a 23% increase in the odds of prediabetes diagnosis. Additionally, each standard deviation increase in the PGS corresponded to a 43% increase in the odds of incident T2D at one-year follow-up. Using complications and forms of clinical intervention (i.e., lifestyle modification, metformin treatment, or insulin treatment) as proxies for advanced illness we also found statistically significant associations between the T2D PGS and insulin treatment and diabetic neuropathy. Importantly, we were able to replicate many findings in a Hispanic/Latino cohort from our database, highlighting the value of the T2D PGS as a clinical tool for individuals with ancestry other than European. In this group, the T2D PGS provided additional disease risk information beyond that offered by traditional screening methodologies. The T2D PGS also had predictive value for the age of onset and for prediabetes among T2D-negative Hispanic/Latino participants. These findings strengthen the notion that a T2D PGS could play a role in the clinical setting across multiple ancestries, potentially improving T2D screening practices, risk stratification, and disease management., Competing Interests: JA, OSa, OSv, SD, RK, LB, MM, SA, PF, SS, JP and BK are current or former employees of 23andMe, Inc. with financial interest in the company., (Copyright © 2022 Ashenhurst, Sazonova, Svrchek, Detweiler, Kita, Babalola, McIntyre, Aslibekyan, Fontanillas, Shringarpure, Pollard and Koelsch.)

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS., Competing Interests: MHB has received research support, speaking engagement honoraria, advisory board honoraria and travel sponsorship from Biogen Idec, Merck, Novartis, Roche and Sanofi-Genzyme, and is a consulting neurologist for RxMx and is Research Director of the Sydney Neuroimaging Analysis Centre. MB has received travel sponsorship and honoraria from Sanofi-Genzyme, Teva, Novartis, Biogen Idec and Roche. BB has received honoraria as a board member for GlaxoSmithKline, Biogen Idec, ViiV Healthcare and Merck Serono, has received speaker honoraria from ViiV Healthcare, Boehringer Ingelheim, Abbott, Abbvie, and Biogen Idec; has received travel sponsorship from Abbott and ViiV Healthcare, and has received research support funding from EI Lilly, GlaxoSmithKline, ViiV Healthcare and Merck Serono. FB has received speaker's honoraria from Biogen-Idec and EMD Serono. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. HB has received honoraria for serving on scientific advisory boards for Biogen Idec, Novartis and Sanofi-Genzyme, has received conference travel sponsorship from Novartis and Biogen Idec, has received honoraria for speaking and acting as Chair at educational events organised by Novartis, Biogen Idec, Medscape and Merck Serono, serves on steering committees for trials conducted by Biogen Idec and Novartis, is chair (honorary) of the MSBase Foundation, which has received research support from Merck Serono, Novartis, Biogen Idec, Genzyme Sanofi and CSL Biopharma and has received research support form Merck Serono. WC has been the recipient of travel sponsorship from, and provided advice to, Bayer Schering Pharma, Biogen-Idec, Novartis, Genzyme, Sanofi-Aventis, BioCSL and Merck-Serono. RD has received research funding from the National Health and Medical Research Council, MS Research Australia, Star Scientific Foundation, Pfizer Neuroscience, Tourette Syndrome Association, University of Sydney, and the Petre Foundation and has received honoraria from Biogen-Idec and Bristol-Myers Squibb as an invited speaker. MF-P has received travel sponsorship from Biogen Australia and New Zealand. RH has received honoraria, educational support and clinic funding from Novartis, Biogen Idec, Genzyme and BioCSL. AGKK has received scientific consulting fees and/or lecture honoraria from Bayer, BioCSL, Biogen-Idec, Genzyme, Lgpharma, Merck, Mitsubishi Tanabe Pharma, NeuroScientific Biopharmaceuticals, Novartis, Roche, Sanofi-Aventis, and Teva. TK has received travel sponsorship from Novartis, BioCSL, Novartis, Merck Serono and Biogen Idec, has received speaker honoraria from Biogen Idec, BioCSL, Merck Serono, Teva, Genzyme and Novartis, has received research support from Biogen Idec, Genzyme, GlaxoSmithKline, Bayer-Schering and Merck Serono, and has received scientific consulting fees from GlaxoSmithKline China, Biogen-Idec and Novartis. JK has received remuneration for advisory board activities and presentations from Bayer Healthcare, Biogen Idec, BioCSL, Genzyme and Novartis. CK has received travel support, honoraria and advisory board payments from Biogen Idec, Bayer, Genzyme, Novartis and Serono. JL-S has received unencumbered funding as well as honoraria for presentations and membership on advisory boards from Sanofi Aventis, Biogen Idec, Bayer Health Care, CSL, Genzyme, Merck Serono, Novartis Australia and Teva. RM has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, CSL, Merck-Serono, Novartis, and Sanofi-Genzyme. MM has received travel sponsorship, honoraria, trial payments, research and clinical support from Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, and Sanofi Aventis Genzyme. DM has received honoraria for attendance at advisory boards from Biogen-Idec and Novartis, and travel sponsorship from Bayer-Schering, Biogen-Idec, and Sanofi-Genzyme. PM has received honoraria or travel sponsorship from Novartis, Sanofi-Aventis and Biogen Idec. JP has received travel sponsorship, honoraria for presentations and membership on advisory boards from Biogen Idec and Novartis and Sanofi Aventis. JDP has received honoraria for seminars or advisory boards from Teva, Biogen, Sanofi-Genzyme, Novartis, Merck, Bayer and research grants or fellowships from Merck, Novartis, Bayer, Biogen, Sanofi-Genzyme, and Teva. SR has received honoraria for advisory consultancy from UCB and speaker's honoraria from Biogen Idec. SWR has received travel sponsorship, honoraria, trial payments, research and clinical support from Aspreva, Baxter, Bayer Schering, Biogen Idec, BioCSL, Genzyme, Novartis, Sanofi Aventis Genzyme and Servier, and is a director of Medical Safety Systems Pty Ltd. CPS has received travel sponsorship from Biogen Idec, Novartis and Bayer-Schering. IS has received remuneration for Advisory Board activities from Biogen, CSL, and Bayer Schering and educational activities with Biogen, CSL and travel sponsorship from Biogen, Novartis and Bayer Schering. JMS has received honoraria for lectures and participation in advisory boards, and travel sponsorship from Novartis, BioCSL, Genzyme, and Biogen Idec. BT has received travel sponsorship from Novartis and Bayer Schering. AV and the University of Oxford hold patents and receive royalties for antibody testing. PW and the University of Oxford hold patents for antibody assays and have received royalties, has received honoraria from Alexion, Biogen Idec F. Hoffmann-La Roche, Retrogenix, UBC and Euroimmun AG, and travel grants from the Guthy-Jackson Charitable Foundation. EW has received honoraria for participation in advisory boards from Biogen-Idec and Novartis, travel sponsorship from Biogen-Idec, Bayer-Schering and Teva and is an investigator in clinical trials funded by Biogen-Idec and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Clarke, Arnett, Bukhari, Khalilidehkordi, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

Rationale & Objective: The relation of vascular stiffness, endothelial function, and kidney function is incompletely elucidated in African Americans. Our hypothesis was that increased vascular stiffness and endothelial dysfunction are associated with low estimated glomerular filtration rate (eGFR) and albuminuria in African Americans., Study Design: Cross-sectional cohort analysis of data from the Jackson Heart Study., Settings & Patients: 2,244 Jackson Heart Study participants (2012-2017 after Exam 3) who had undergone noninvasive hemodynamic assessment using arterial tonometry., Predictors: Baseline carotid-femoral pulse wave velocity, pulsatile hemodynamics forward wave amplitude, and hyperemic brachial artery flow were measured. Reduced eGFR was defined as eGFR between 15 and 60 mL/min/1.73 m 2 ., Outcomes: Prevalent albuminuria, urinary albumin-creatinine ratio., Analytical Approach: 2-sample t test for continuous variables and χ 2 test for categorical variables in addition to logistic and linear regression models to assess the risk for chronic kidney disease with each proposed hemodynamic variable., Results: Among 2,244 participants, mean age was 66 ± 11 years and 64% were women. Reduced eGFR was present in 233 (10.4%), and elevated urinary albumin-creatinine ratio, in 232 (10.4%). In multivariable-adjusted analyses, higher carotid-femoral pulse wave velocity was associated with the presence of reduced eGFR (OR, 1.37 [95% CI, 1.08-1.75] per SD; P  = 0.01) and with prevalent albuminuria (OR, 1.66 [95% CI, 1.32-2.11]; P  < 0.001). Higher forward wave amplitude was significantly associated with prevalent albuminuria (OR, 1.37 [95% CI, 1.14-1.65]; P  = 0.001)., Limitations: Cross-sectional analyses cannot inform causality., Conclusions: Higher arterial stiffness and pulsatility are associated with higher odds of reduced eGFR in African Americans. Future studies should focus on whether improving arterial stiffness contributes to kidney protection in African Americans., (© 2021 The Authors.)

Objectives: We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH., Design: Cross-sectional, cohort study., Setting: Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000-2004 enrolled residents of the Jackson, Mississippi metropolitan area., Participants: Participants from the JHS with analysable ECGs recorded in 2009-2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors' magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured., Outcome: Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke., Results: In adjusted mixed linear models, women had a smaller spatial QRS-T angle (-12.2 (95% CI -19.4 to -5.1)°; p=0.001) and SAI QRST (-29.8 (-39.3 to -20.3) mV*ms; p<0.0001) than men, but larger SVG azimuth (+16.2(10.5-21.9)°; p<0.0001), with a significant random effect between families (+20.8 (8.2-33.5)°; p=0.001). SAI QRST was larger in women with CVD as compared with CVD-free women or men (+15.1 (3.8-26.4) mV*ms; p=0.009). Men with CVD had a smaller T area (by 5.1 (95% CI 1.2 to 9.0) mV*ms) and T peak magnitude (by 44 (95%CI 16 to 71) µV) than CVD-free men. T vectors pointed more posteriorly in women as compared with men (peak T azimuth + 17.2(8.9-25.6)°; p<0.0001), with larger sex differences in T azimuth in some families by +26.3(7.4-45.3)°; p=0.006., Conclusions: There are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Almost half of African American (AA) men and women have cardiovascular disease (CVD). Detection of prevalent CVD in community settings would facilitate secondary prevention of CVD. We sought to develop a tool for automated CVD detection., Methods and Results: Participants from the Jackson Heart Study (JHS) with analysable electrocardiograms (ECGs) ( n =3679; age, 6212 years; 36% men) were included. Vectorcardiographic (VCG) metrics QRS, T, and spatial ventricular gradient vectors magnitude and direction, and traditional ECG metrics were measured on 12-lead ECG. Random forests, convolutional neural network (CNN), lasso, adaptive lasso, plugin lasso, elastic net, ridge, and logistic regression models were developed in 80% and validated in 20% samples. We compared models with demographic, clinical, and VCG input (43 predictors) and those after the addition of ECG metrics (695 predictors). Prevalent CVD was diagnosed in 411 out of 3679 participants (11.2%). Machine learning models detected CVD with the area under the receiver operator curve (ROC AUC) 0.690.74. There was no difference in CVD detection accuracy between models with VCG and VCG + ECG input. Models with VCG input were better calibrated than models with ECG input. Plugin-based lasso model consisting of only two predictors (age and peak QRS-T angle) detected CVD with AUC 0.687 [95% confidence interval (CI) 0.6250.749], which was similar ( P =0.394) to the CNN (0.660; 95% CI 0.5970.722) and better ( P <0.0001) than random forests (0.512; 95% CI 0.4930.530)., Conclusions: Simple model (age and QRS-T angle) can be used for prevalent CVD detection in limited-resources community settings, which opens an avenue for secondary prevention of CVD in underserved communities., (The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( p < 0.001) and area postrema relapses ( P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD., (Copyright © 2020 Khalilidehkordi, Clarke, Arnett, Bukhari, Jimenez Sanchez, O'Gorman, Sun, Prain, Woodhall, Silvestrini, Bundell, Abernethy, Bhuta, Blum, Boggild, Boundy, Brew, Brown, Brownlee, Butzkueven, Carroll, Chen, Coulthard, Dale, Das, Fabis-Pedrini, Fulcher, Gillis, Hawke, Heard, Henderson, Heshmat, Hodgkinson, Kilpatrick, King, Kneebone, Kornberg, Lechner-Scott, Lin, Lynch, Macdonell, Mason, McCombe, Pereira, Pollard, Ramanathan, Reddel, Shaw, Spies, Stankovich, Sutton, Vucic, Walsh, Wong, Yiu, Barnett, Kermode, Marriott, Parratt, Slee, Taylor, Willoughby, Brilot, Vincent, Waters and Broadley.)

Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Although the pathogenesis of MS remains unknown, it is widely regarded as an autoimmune disease mediated by T-lymphocytes directed against myelin proteins and/or other oligodendrocyte epitopes., Methods: In this study we investigated the gene expression profiles of peripheral blood cells from patients with RRMS during the relapse and the remission phases utilizing gene microarray technology. Dysregulated genes encoded in regions associated with MS susceptibility from genomic screens or previous transcriptomic studies were identified. The proximal promoter region polymorphisms of two genes were tested for association with disease and expression level., Results: Distinct sets of dysregulated genes during the relapse and remission phases were identified including genes involved in apoptosis and inflammation. Three of these dysregulated genes have been previously implicated with MS susceptibility in genomic screens: TGFbeta1, CD58 and DBC1. TGFbeta1 has one common SNP in the proximal promoter: -508 T>C (rs1800469). Genotyping two Australian trio sets (total 620 families) found a trend for over-transmission of the T allele in MS in females (p < 0.13). Upregulation of CD58 and DBC1 in remission is consistent with their putative roles in promoting regulatory T cells and reducing cell proliferation, respectively. A fourth gene, ALOX5, is consistently found over-expressed in MS. Two common genetic variants were confirmed in the ALOX5 putative promoter: -557 T>C (rs12762303) and a 6 bp tandem repeat polymorphism (GGGCGG) between position -147 and -176; but no evidence for transmission distortion found., Conclusion: The dysregulation of these genes tags their metabolic pathways for further investigation for potential therapeutic intervention.

Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract.

Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing-remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P < 10(-4), chi(2)). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One interleukin 7 receptor (IL7R) promoter single nucleotide polymorphism (SNP), -504 C, was undertransmitted in PPMS trios (P = 0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P = 0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P < 0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.

Hereditary sensory neuropathy type I (HSN I) is a group of dominantly inherited degenerative disorders of peripheral nerve in which sensory features are more prominent than motor involvement. We have described a new form of HSN I that is associated with cough and gastroesophageal reflux. To map the chromosomal location of the gene causing the disorder, a 10-cM genome screen was undertaken in a large Australian family. Two-point analysis showed linkage to chromosome 3p22-p24 (Zmax=3.51 at recombination fraction (theta) 0.0 for marker D3S2338). A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266.

Over a 33-year period, 260 patients (< 17 years of age; 119 males, 141 females) from New South Wales, Australia who had peripheral neuropathies confirmed by nerve biopsy, were studied. Of these, 50 infants presented with symptoms or signs of neuropathy under 1 year of age: including 24 patients with demyelinating neuropathies and 21 axonal neuropathies; a further five patients had spinal muscular atrophy with associated secondary sensory axonopathy. Nineteen infants had hereditary motor sensory neuropathy, of whom 13 had myelin protein mutations confirmed by molecular genetic studies. Peripheral neuropathy is not an unusual diagnosis in infancy. Awareness of this association will aid early diagnosis and prognosis as well as facilitate interventional patient management.

Muscle pathology in McLeod syndrome is usually mild; patchy necrotic or regenerating fibres, occasional internal nuclei, and the absence of an inflammatory cell infiltrate are the usual findings. We report on a 29 year old man presenting with chronic fatiguability and excessive sweating in whom an open quadriceps muscle biopsy demonstrated grouped necrotic fibres accompanied by striking patchy mononuclear cell infiltrates. The diagnosis of McLeod syndrome was made on the basis of red blood cell acanthocytosis, raised serum creatine kinase, and weak expression of Kell blood group antigens. The quadriceps muscle infiltrate consisted principally of histologically typical macrophages. These cells had prominent nucleoli, displayed numerous mitoses, and were strongly CD68+. A small population of typical CD3+, CD43+ lymphocytes was also present. In addition, a small population of large atypical CD3+ cells was noted. Immunoperoxidase stains for CD20, CD30, CD79a, and CD56 were negative. Immunocytochemical studies for the common muscular dystrophies were normal. The muscle biopsy findings highlight a potential for confusion of this condition with idiopathic polymyositis. The expanding range of muscle pathology reported in McLeod syndrome, to which this case adds, may reflect variable involvement of the XK gene on chromosome Xp21, or of the adjacent loci of Duchenne muscular dystrophy and chronic granulomatous disease.

Objectives: To describe the neuropathological features of clinical syndromes associated with tomacula or focal myelin swellings in sural nerve biospies and to discuss possible common aetiopathological pathways leading to their formation in this group of neuropathies., Methods: Fifty two patients with sural nerve biopsies reported to show tomacula or focal myelin swellings were reviewed, light and electron microscopy were performed, and tomacula were analysed on teased fibre studies. Molecular genetic studies were performed on those patients who were available for genetic testing., Results: Thirty seven patients were diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), four with hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1), four with HMSN with myelin outfolding (CMT4B), three with IgM paraproteinemic neuropathy, three with chronic inflammatory demyelinating polyneuropathy (CIDP), and one with HMSN III (CMT3)., Conclusions: Most of these syndromes were shown to be related to genetic or immunological defects of myelin components such as peripheral myelin protein 22 (PMP22), myelin protein zero (P0), or myelin associated glycoprotein (MAG). These proteins share the HNK-1 epitope which has been implicated in cell adhesion processes. Impaired myelin maintenance may therefore contribute to the formation of tomacula and subsequent demyelination.

The cellular and microvascular responses of JC Lewis rats to an intravenous injection of activated T cells specific for ovalbumin were examined with the retinal whole mount technique. The retina was examined at various times post-injection (pi) with the use of antibodies to the alphabeta T cell receptor (TCR) or to major histocompatibility complex class II (MHC II), the monoclonal antibody ED1, and intravascular tracers. By 12 hours pi, small numbers of TCR(+), ED1(+), and MHC II(+) cells were present within the lumen of retinal vessels, and minor breakdown of the blood-retinal barrier (BRB) and microglial activation were evident. The intensity of these responses had increased by 1 day pi, when small numbers of TCR(+) cells had also undergone extravasation. By 2 to 3 days pi, the numbers of TCR(+), ED1(+), and MHC II(+) cells in the retinal parenchyma had increased, but the BRB breakdown and microglial activation had subsided. Thus, in the absence of target antigen, activated T cells induced limited and transient breakdown of the BRB, microglial activation, and the extravasation of ED1(+), MHC II(+) monocytes. In contrast, the retina of rats that received an intraocular injection of ovalbumin in addition to the intravascular injection of T cells showed massive cellular recruitment and breakdown of the BRB. These results indicate that an increase in the number of activated T cells in the circulation, such as that which occurs during viral or bacterial infection, has the potential to result in transient breakdown of the BRB and a mild local microglial response.

Previous studies have shown that activated T cells can successfully cross endothelial barriers and will accumulate in tissue which contains their specific antigen. Myelin specific T cells (e.g. myelin basic protein specific) are recognized to play an important role in the induction of experimental autoimmune demyelinating disease of the CNS and have been shown to induce blood-brain barrier breakdown effectively. In this study we injected T cells reactive to a non-neural antigen (ovalbumin) systemically into Lewis rats and caused them to accumulate in the thoracic dorsal column by a prior injection of ovalbumin. Selected rats were given systemic demyelinating antibody, antimyelin oligodendrocyte antibody (anti-MOG antibody), to provide evidence of permeability changes to the blood-brain barrier. These animals were compared with control rats given systemic anti-P0 monoclonal antibody and to other rats given a direct micro-injection (3 microliters) of anti-MOG antibody into the thoracic dorsal column. All animals were monitored by serial neurophysiological studies and by histological examination. Direct anti-MOG antibody injection produced a focal block in conduction at the injection site and a large circumscribed area of primary demyelination with axonal preservation within the dorsal column. An even more profound conduction block and more extensive plaque-like region of demyelination were seen in animals given antigen, activated T cells and systemic antibody. However, animals given antigen and T cells without relevant antibody did not show conduction impairment or demyelination, except when very large numbers of T cells were given; such rats developed severe irreversible axonal damage. This study demonstrates the blood-brain barrier is disrupted by activated T cells of non-neural specificity and allows large plaque-like regions of demyelination to form in the presence of circulating antimyelin antibody. The relevance of this finding to multiple sclerosis is discussed.

MRI was performed on the spinal roots, brachial and lumbar plexuses of 14 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Hypertrophy of cervical roots and brachial plexus was demonstrated in eight cases, six of whom also had hypertrophy of the lumbar plexus. Of 11 patients who received gadolinium, five of six cases with hypertrophy and one of five without hypertrophy demonstrated enhancement. All patients with hypertrophy had a relapsing-remitting course and a significantly longer disease duration. Gross onion-bulb formations were seen in a biopsy of nerve from the brachial plexus in one case with clinically evident nodular hypertrophy. We conclude that spinal root and plexus hypertrophy may be seen on MRI, particularly in cases of CIDP of long duration, and gadolinium enhancement may be present in active disease.

A single injection of Escherichia coli lipopolysaccharide (LPS; intraperitoneally [i.p.] and intravenously [i.v.]) reliably induces peripheral nerve disturbances in the hindlimbs of inbred Australian albino Wistar (AaW) rats. In the series of experiments presented here, we aimed to characterize this syndrome by examining electrophysiologic, immunologic, and immunochemical features. The LPS-induced neurologic sequelae in AaW rats were transient, at least partly reversible by drug treatment, and were not associated with any detectable neuropathologic findings by light microscopy. Neurologic sequelae were prevented by administration of dexamethasone and by pretreatment with the macrophage inhibitor gadolinium chloride, suggesting that they were caused by LPS-induced activation of peripheral macrophages. Sequelae were associated with early decreases in compound muscle-action potential amplitudes, indicating impaired functioning of either proximal sciatic nerve axons and/or neuromuscular synapses. Spinal somatosensory-evoked potential latencies also were increased, indicating impaired somatosensory function at the sciatic nerve, dorsal roots, spinal cord, and/or postsynaptic interneurons, although the precise location of impairment could not be delineated. Similarities between this syndrome and immune-mediated polyneuropathies in humans are discussed.

Lymphotoxin (LT) is widely regarded as a proinflammatory cytokine with activities equivalent to tumor necrosis factor (TNF). The contribution of LT to experimental autoimmune encephalomyelitis (EAE) was examined using TNF/LTalpha-/- mice, TNF-/- mice, and a new LTalpha-/- line described here. All mice were generated directly in the C57BL/6 strain and used for the preparation of radiation bone marrow chimeras to reconstitute peripheral lymphoid organs and restore immunocompetence. This approach overcame the problems related to the lack of lymph nodes that results from LTalpha gene targeting. We show here that when LT is absent but TNF is present, EAE progresses normally. In contrast, when TNF is absent but LT is present, EAE is delayed in onset and inflammatory leukocytes fail to move normally into the central nervous system parenchyma, even at the peak of disease. In the absence of both cytokines, the clinical and histological picture is identical to that seen when TNF alone is deficient, including demyelination. Furthermore, the therapeutic inhibition of TNF and LTalpha with soluble TNF receptor in unmanipulated wild-type or TNF-/- mice exactly reproduces these outcomes. We conclude from these studies that TNF and LT are functionally distinct cytokines in vivo, and despite sharing common receptors, show no redundancy of function nor mutual compensation.

Tumor necrosis factor (TNF)-dependent sites of action in the generation of autoimmune inflammation have been defined by targeted disruption of TNF in the C57BL/6 mouse strain. C57BL/6 mice are susceptible to an inflammatory, demyelinating form of experimental autoimmune encephalomyelitis (EAE) induced by the 35-55 peptide of myelin oligodendrocyte glycoprotein. Direct targeting of a strain in which EAE was inducible was necessary, as the location of the TNF gene renders segregation of the mutated allele from the original major histocompatibility complex by backcrossing virtually impossible. In this way a single gene effect was studied. We show here that TNF is obligatory for normal initiation of the neurological deficit, as demonstrated by a significant (6 d) delay in disease in its absence relative to wild-type (WT) mice. During this delay, comparable numbers of leukocytes were isolated from the perfused central nervous system (CNS) of WT and TNF-/- mice. However, in the TNF-/- mice, immunohistological analysis of CNS tissue indicated that leukocytes failed to form the typical mature perivascular cuffs observed in WT mice at this same time point. Severe EAE, including paralysis and widespread CNS perivascular inflammation, eventually developed without TNF. TNF-/- and WT mice recovered from the acute illness at the same time, such that the overall disease course in TNF-/- mice was only 60% of the course in control mice. Primary demyelination occurred in both WT and TNF-/- mice, although it was of variable magnitude. These results are consistent with the TNF dependence of processes controlling initial leukocyte movement within the CNS. Nevertheless, potent alternative mechanisms exist to mediate all other phases of EAE.

The clinical, electrophysiological and pathological features and prognosis of 25 patients with vasculitis selectively affecting the peripheral nervous system were evaluated. Although most patients had a history of mononeuritis multiplex or an asymmetrical neuropathy six out of 25 had a symmetrical neuropathy, both clinically and on neurophysiological testing, by the time of presentation. There were no signs of accompanying systemic vasculitis in any of the patients and serological abnormalities were limited to an elevated erythrocyte sedimentation rate (ESR) in nine out of 21 patients and low titre anti-nuclear antibodies in four out of 20 patients. Most patients had a necrotizing vasculitis on nerve biopsy, although in some cases the diagnosis was made on the association of inflammatory cell infiltrates with extensive axonal degeneration and immune complex deposition on immunofluorescence studies. The mean time from symptom onset to diagnosis was 46 weeks. All patients were treated with corticosteroids and most with additional immunosuppressive therapy. In contrast to vasculitic neuropathy associated with systemic vasculitis the prognosis was good with 24 out of 25 survivors at a mean of 176 weeks follow-up having a mean improvement of 1.4 units on a six-point disability scale.

The RNA world hypothesis is founded on the idea of an RNA replicase, or self-replicating RNA molecule, and presupposes the later emergence of ribozymes capable of catalyzing the synthesis of peptides. The recent demonstrations of ribozyme-catalyzed template-directed primer extension, and of ribozyme-catalyzed amide bond synthesis, confirm the plausibility of the RNA world, and highlight the steps that remain to be demonstrated in the laboratory.

Four patients are described who developed sensorimotor neuropathy while being treated with simvastatin and had complete or partial resolution of clinical abnormalities after withdrawal of treatment. In one case onset was within days of commencing treatment, but in two cases symptoms did not develop for two years. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Clinical evidence of proximal and distal weakness and muscle fasciculations and persistent abnormalities of sensory conduction after recovery suggest the possibility of toxic damage to anterior horn cells and dorsal root ganglia. Thirty eight other cases with symptoms suggestive of peripheral neuropathy have been reported to the Australian Adverse Drug Reactions Advisory Committee, 22 of whom recovered after cessation of treatment; in five cases there was recurrence after re-exposure to the drug. Simvastatin should be considered among the causes of peripheral neuropathy, and the drug should be withdrawn if patients receiving it develop muscle weakness or sensory disturbances.

Five patients with peripheral neuropathy and benign IgG monoclonal paraproteinemia are reported, all of whom had a sensorimotor neuropathy with a remitting and relapsing course. The serum paraprotein level did not correlate with the patient's clinical status. Electrophsyiological studies showed marked slowing of conduction velocity and conduction block in four of the patients and mild slowing in the other. Sural nerve biopsies demonstrated a demyelinating neuropathy with inflammatory cell infiltrates in each of the five patients. Three of the patients had evidence of myelin/Schwann cell reactivity on immunofluorescence studies and in all nerves dense expression of major histocompatability complex class I and II molecules was evident within the endoneurium, on invading mononuclear cells, endothelial cells and Schwann cells. All the patients responded to treatment, plasmapheresis being particularly effective. Four patients have achieved prolonged remissions after all treatment had ceased. These five cases of peripheral neuropathy and IgG paraproteinaemia were identical in their clinical, electrophysiological and pathological features to patients with chronic inflammatory demyelinating polyneuropathy.

Electrophysiological and histological studies of peripheral nerve were performed in 24 Lewis rats with experimental allergic neuritis (EAN) in which disease had been induced by a single myelin and adjuvant inoculation in one footpad. Demyelination was demonstrated in transverse nerve sections from ventral roots, proximal sciatic nerves and also in distal plantar nerves. Histological and electrophysiological assessments showed that injected limbs were more affected than uninjected limbs. Neurophysiological studies demonstrated two distinct patterns of conduction failure based upon proximal/distal compound muscle action potential (CMAP) amplitude ratios in both uninjected and injected limbs. Slightly more than half of all nerve trunks showed a mildly reduced distal CMAP amplitude irrespective of stimulus origin. The rest displayed a more severe reduction of distal amplitude that was length-dependent, becoming smaller with proximal stimulation. Histological lesions in plantar nerves were often more severe than those in proximal sciatic nerves or ventral roots. Axonal degeneration was an uncommon finding. This study has demonstrated patterns of peripheral nerve conduction impairment similar to those reported in patients with inflammatory demyelinating neuropathy. Moreover, it has shown that a low distal CMAP amplitude may result from demyelination of distal motor nerve segments and not necessarily from axonal degeneration.

Eight patients with chronic inflammatory demyelinating polyneuropathy, five of whom had an associated paraproteinaemia, were treated with cyclosporin in a pilot, uncontrolled study for periods up to three and a half years after failing to respond adequately to corticosteroid and azathioprine therapy and plasmapheresis. Three patients had an excellent response, two with complete remission. In other cases it was possible to reduce the corticosteroid therapy and frequency of plasmapheresis. There were no serious complications of the treatment.

HLA typing of 71 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) showed an overall increase in frequencies of HLA-A3, -B7, -DR2 as well as concomitantly decreased frequencies of HLA-44 and DR7. The strongest associations were seen with HLA-DR2, -DR7 and -B44 in CIDP overall, although they did not reach statistical significance.

The effect of IgG immunoadsorption upon the course of chronic experimental allergic neuritis (EAN) is described. Miniature membrane plasma separators coupled with a Protein A (PA)-Sepharose immunoadsorbent column were used to perform upon conscious rabbits 5 IgG immunoadsorption treatments over 6 days. Quantitation of anti-myelin IgG and IgM by ELISA revealed that 55-65% of plasma IgG was removed per treatment. Rapid post-treatment antibody rebound was observed for anti-myelin IgG although no antibody overshoot above control levels could be observed. Anti-myelin IgM levels remained relatively unaffected by PA immunoadsorption. Comparisons of clinical scores between control and treatment animals showed that IgG immunoadsorption was significantly beneficial (day 1 post-treatment p less than 0.001; day 2 post-treatment p less than 0.05). However, rapid relapse was observed in all treatment animals such that by day 3 post-treatment no significant clinical difference between control and treatment groups could be observed. IgG immunoadsorption suppresses the clinical progression of chronic EAN in a manner similar to that seen with plasma exchange. This finding suggests that antibody modulates early disease pathogenesis.

The effect of intravenous fresh frozen plasma (FFP) and artificial plasma infusions upon the clinical course of chronic experimental allergic neuritis (EAN) in the rabbit was investigated. A total of 12 animals allocated to treatment groups received rabbit FFP or a gelatin plasma expander Haemaccel (Hoechst) and were compared to 13 control non-treated animals. Animals receiving Haemaccel at a rate of 15 ml/kg/day for 7 days showed no significant clinical benefit at any stage. However, animals receiving 15 ml/kg/day FFP for 8 days showed significant clinical benefit during treatment initiated at the onset of definite neurological symptoms of EAN (Mann-Whitney U test, day 4 post-allocation P less than 0.05; day 6 post-allocation P less than 0.01; day 8 post-allocation P less than 0.05). Relapse was observed after cessation of treatment such that comparisons of clinical scores at day 14 and 22 post-allocation revealed no significant differences. Analysis of plasma anti-myelin IgG levels by ELISA showed that non-immunogenic plasma volume expansion decreased anti-myelin IgG concentrations immediately by an average of 34% but had no long-term effect. In contrast, anti-myelin IgG concentrations in FFP infused animals were significantly decreased, compared to controls, when measured 24 h after the last infusion (Student's t-test P less than 0.05). Identical percentage weight losses for both control and treatment groups post-allocation indicated that this decrease was immunologically mediated and not due to plasma dilution. Similar plasma cortisol concentrations measured in both groups showed no significant artifactual induction of endogenous steroid production. Infusions of FFP during early disease progression are able to mediate clinical remission in animals with chronic EAN.

The case histories of 519 patients with peripheral neuropathy on whom sural nerve biopsy had been performed were reviewed. In 67 patients (50 males, 17 females) (13%) who had symptoms of a symmetrical polyneuropathy for more than one year, the cause remained undiagnosed in spite of intensive investigation. Patients with inflammatory neuropathy were not included, but represented 17% of the whole series. The mean age of onset of symptoms was 50.6 years, and the median time from onset of symptoms to initial investigation was 2 years. Males were affected more commonly than females in a ratio of 3:1. The clinical features in 43 patients were those of a mixed motor and sensory neuropathy, in 17 patients a predominantly sensory neuropathy and in 7 patients a predominantly motor neuropathy. The mean CSF protein was 0.73 g/l and in only six patients was it greater than 1 g/l. Nerve conduction studies most commonly demonstrated mild slowing of motor conduction and impairment of sensory conduction. The usual pathological changes on sural nerve biopsy were those of chronic axonal degeneration. Forty seven patients (70%) were re-examined at intervals of time which ranged from 4 months to 12 years after their initial presentation and nerve biopsy (median, 3 years). As a group, they were only mildly disabled, the condition had a very slowly progressive course and there had been little change in their disability. A possible aetiological factor was found in 17 of the 47 patients (36%) and included malignancy, alcoholism, and benign paraproteinaemia. It is concluded that with intensive investigation the cause of chronic polyneuropathy of duration greater than one year remains undetermined in only about 13% of patients and that continued follow-up is worthwhile since a diagnosis may be established on re-examination.

Seven weeks after he was bitten on the lip by a puppy in the Gambia a patient showed symptons of rabies. Passive and active immunisation was begun three days after the onset of symptons. The evidence indicated that death was a direct consequence of the central nervous system disease rather than any associated complication. Our inability to alter the course of the illness appreciably emphasises the importance of immediate postexposure immunisation in rabies and draws attention to the present lack of effective means of preventing virus replication within the central nervous system.