Body metrics are associated with clinical, free-living, and self-report measures of mobility in a cohort of adults with obesity and multiple sclerosis.

BACKGROUND: Obesity is associated with multiple sclerosis (MS) onset and may contribute to more rapid disability accumulation. Whether obesity impacts mobility in MS is uncertain. Some studies find that obesity in MS is associated with poorer mobility; other studies find no relationship. Discrepant findings may be due to differences in measurement and methodology. In the present study, we employ a comprehensive battery of anthropometric and mobility measures in a sample of people with MS and obesity. METHODS: Participants with MS (N = 74) completed a battery of adiposity measurements (weight, height, waist circumference, and full body dual-energy x-ray absorptiometry [DXA] scans). They also completed validated clinical, free-living (accelerometry), and self-report measures of mobility. Spearman's Rho correlations were used to examine the associations between mobility and obesity measures with Benjamini and Hochberg correction for multiple comparisons. Multiple linear regression was used to examine if adiposity predicted mobility outcomes in people with MS when controlling for age and disease duration. RESULTS: The majority of participants (n = 70) were diagnosed with relapsing-remitting MS and reported mild MS-related disability on the Patient Determined Disease Steps (M = 0.77, SD = 1.1). Median BMI was 35.8 (SD = 5.4). Higher percentage body fat (measured via DXA) was associated with poorer self-reported physical functioning (rs = -0.52, p <0.001), less moderate-to-vigorous physical activity (rs = -0.24, p = 0.04), and worse performance on the Six Minute Walk Test (6MWT; rs = -0.44, p <0.001), the Timed 25 Foot Walk (T25FW; rs = 0.45, p <0.001), and the Timed Up and Go test (TUG; rs = 0.35, p = .003). Higher BMI and waist-to-height ratio (WtHR) were associated with worse outcomes on the 6MWT (BMI; rs = -0.35, p <0.01, WtHR; rs = -0.43, p <0.001), T25FW (BMI; rs = 0.32, p <0.01, WtHR; rs = 0.38, p <0.001), and the SF-36 (BMI; rs = -0.29, p <0.005, WtHR; rs = -0.31, p <0.05). Percentage body fat accounted for an additional 17 % of the variance in the T25FW and 6MWT performance, after controlling for age and disease duration. CONCLUSION: Higher BMI, WtHR, and percentage body fat were associated with lower levels of mobility (T25FW and 6MWT) in people with MS who have class I, class II, and class III obesity. Higher percentage body fat was associated with significantly worse performance on clinical, free-living, and self-report measures of mobility in people with MS even when accounting for participant age and disease duration. These findings suggest that people with MS and obesity may show improved mobility with weight loss.

Spectroscopic gas detection using a Bragg grating - stabilized external cavity laser, custom written in planar integrated silica-on-silicon.

We present the development of an external cavity Bragg grating stabilized laser for tunable diode laser spectroscopy (TDLS). Our design uses a planar integrated silica-on-silicon platform incorporating a custom written Bragg grating as the wavelength-selective element of the laser cavity. We have developed a prototype singlemode laser at 1651 nm and performed a detailed characterization of its performance for the purpose of spectroscopic measurement of methane at this wavelength using a 25 cm path-length single-pass cell. Mode hop-free tuning of 0.13 nm has been demonstrated at frequencies of up to 10 kHz. A single-point limit of detection for TDLS of ΔI/I0 = 8.3 × 10-5 AU was achieved, which is consistent with the performance of standard distributed feedback lasers. The new device exhibits a side-mode suppression ratio of -40 dB and a low RIN of <-150 dB/Hz, and thus avoids the high levels of noise or instability normally associated with larger, mechanically driven external cavity lasers. The silica-on-silicon platform has the potential for low-volume manufacturing of special lasers at the custom wavelengths required for gas detection, without the need for investment in foundry solutions.

The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics.

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T.

BACKGROUND: Disability levels for patients with secondary progressive multiple sclerosis (SPMS) often worsen despite a stable MRI T(2) lesion burden. The presence of oxidative stress in the absence of measurable inflammation could help explain this phenomenon. In this study, the assessment of an in vivo marker of oxidative stress, cerebral glutathione (GSH), using magnetic resonance chemical shift imaging (CSI) is described, and GSH levels were compared in patients with SPMS and healthy controls. OBJECTIVE: To assess whether GSH, a key antioxidant in the brain, is lower in the SPMS patients compared to matched controls. METHODS: Seventeen patients with SPMS (Expanded Disability Status Scale=4.0-7.0; length of MS diagnosis=19.4 ± 7 years) and 17 age- and gender-matched healthy controls were studied. GSH levels were measured in the fronto-parietal regions of the brain using a specially designed magnetic resonance spectroscopy technique, CSI of GSH, at 3T. RESULTS: The levels of GSH were lower for SPMS patients than for controls, the largest reduction (18.5%) being in the frontal region (p=0.001). CONCLUSION: The lower GSH levels in these patients indicate the presence of oxidative stress in SPMS. This process could be at least partially responsible for ongoing functional decline in SPMS.

Cognitive impairment in patients with multiple sclerosis: association with the APOE gene and promoter polymorphisms.

BACKGROUND: Studies examining the epsilon4 allele of the APOE gene as a factor affecting the severity of multiple sclerosis (MS) have yielded conflicting results. The focus of these studies on physical disability to the neglect of cognitive impairment is surprising in light of the associations between the epsilon4 allele and other dementia conditions. Only two studies examine the relationship between the epsilon4 allele and cognitive impairment. METHODS: A neuropsychological test battery was administered to 263 MS patients, and their current disability status was evaluated. Genotypes were determined for APOE epsilon and for two promoter region polymorphisms (-219 G/T and -491 A/T). RESULTS: Although effects were generally weak, female patients with the -491 AA genotype had a later age of disease onset, lower disability scores, and somewhat higher scores on the cognitive battery. Male patients with the epsilon2 allele had lower disability and higher scores on the cognitive battery. The epsilon4 allele was not related to physical disability, and there was no difference between epsilon4+ and epsilon4--patients in overall cognitive performance. However, when patients with severe cognitive impairment were identified, a greater proportion (52%) of these patients had the epsilon4 allele than those in the unimpaired group (27%). CONCLUSION: An association with the epsilon4 allele was evident in this study, but only in cases of severe cognitive impairment.

Prevalence of multiple sclerosis in a residential area bordering an oil refinery.

BACKGROUND: Community concerns about a potential excess of multiple sclerosis (MS) prompted this study. OBJECTIVE: To determine the period prevalence of MS in a community bordering a closed oil refinery and a control community. METHODS: Cases seen by a neurologist during 1998 to 2001 were obtained from area neurologists and hospital discharge data. Population data were obtained from the year 2000 US Census. Patient data were abstracted by a trained abstractor onto a standardized report form. A consulting neurologist reviewed the form and made a final diagnosis using the Poser criteria plus the category of presumed. Age-adjusted prevalence rates and rates of agreement were calculated. RESULTS: The direct age-adjusted period prevalence for both sexes and all races for the entire study area was 113 per 100,000 (95% CI = 93 to 136). For white subjects only, the prevalence was 123 per 100,000 (95% CI = 102 to 147). With use of an indirect method of age adjustment, the number of observed cases in the community bordering the refinery was similar to the number of cases expected (standardized morbidity ratio = 130.8, 95% CI = 62.3 to 199.3), based on rates from the comparison area. The agreement between the treating neurologist (for definite plus probable cases) and the consulting neurologist (for definite plus probable plus presumed cases) was good (kappa = 0.5733). CONCLUSIONS: The prevalence of multiple sclerosis (MS) for this area was generally consistent with prevalence estimates calculated in previous studies in other areas. No significant excess was seen in the exposed area. MS was more prevalent in females than in males. The overall agreement between the consulting and treating neurologist was good.

Depression during exacerbations in multiple sclerosis: the importance of uncertainty.

The following correlates of depression were examined in a sample of 166 patients with clinically definite relapsing-remitting (n=140) or secondary progressive (n=26) multiple sclerosis: (a) the present state of the patients' illness (i.e., whether or not they were currently experiencing an exacerbation of their symptoms); (b) their level of uncertainty concerning their illness; and (c) their strategies for coping with their illness. A current exacerbation in symptoms, greater uncertainty of illness, and greater use of emotion-centered forms of coping were all related to depression. Multivariate analyses revealed that uncertainty of illness played a pivotal role as a mediating variable. Exacerbations in illness appeared to heighten patients' levels of uncertainty, and it was largely through this heightened uncertainty that the increases in depression came about.

The relationship between disability and depression in multiple sclerosis: the role of uncertainty, coping, and hope.

The relationship between disability and depression was studied in 188 patients with clinically definite multiple sclerosis (MS). Patients were administered the Zung Self-Rating Depression Scale, Ways of Coping, Uncertainty of Illness Scale, and Hope Scale during their regular clinic appointments. Their current level of disability was rated by the attending physician using the Expanded Disability Status Scale. Even when the depression measure was corrected for items overlapping with other symptoms or consequences of MS, depression was correlated with disability. Depression was also correlated with an array of psychological variables, including uncertainty concerning ones illness, hope, and the use of various emotion-centered, though not problem-centered coping strategies. Multiple regression analyses revealed that none of these psychological correlates mediated or moderated the relationship between disability and depression. Instead, disability, uncertainty, hope, and emotion-centered coping were significant independent predictors of depression, together accounting for approximately 40% of the variance in patients' self-reported depression. The relationship between disability and depression in MS is usually interpreted as evidence that depression is psychogenic and reactive to the demands and limitations of this disease. The demonstration that this relationship is not diminished when an array of potentially intervening psychological variables are included in the analysis raises questions concerning the validity of this interpretation.

A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis.

Chronic progressive multiple sclerosis (MS) is a debilitating disease that is often refractory to treatment. We have previously published a pilot study using a single 2-week course of the iron chelating drug, desferrioxamine (DFO), as a candidate drug for treatment of this form of MS. In this study, we gave 9 patients up to 8 courses of this regimen over 2 years. The patients tolerated the medication well. During the study, 1 patient improved, 3 remained stable, and 5 worsened by 0.5 on the Kurtzke expanded disability status scale (EDSS). These results suggest that, while the drug is well tolerated, no effect on disease progression can be identified at this dosage level. A more continuous dosage schedule could be studied as a candidate for treatment in this disease process.

Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern.

In order to investigate the associations between fatigue and depression, disability, and disease subtype, 207 individuals with clinically definite Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung Self-rating Depression Scale during a regular clinic appointment. Their current level of disability was established using the Expanded Disability Status Scale. Fatigue and depression were highly correlated (r=0.58), even when the depression measure was corrected for items overlapping with fatigue and other symptoms or consequences of MS (r=0.44). Fatigue and disability were also correlated (r=0.33). Multiple regression revealed that both depressed mood and disability were significant predictors of fatigue, together accounting for approximately 23% of the variance in patients' self-reported fatigue. The combined groups of primary progressive (n=45) and secondary progressive patients (n=25) appeared to have higher fatigue scores than relapsing-remitting patients (n=137). However, an analysis of covariance revealed that this apparent difference was in fact attributable almost exclusively to differences in disability among the three subtypes of MS. Other reports of differences in fatigue between subtypes of MS should be re-examined in light of this finding.

Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients.

The concentrations of ferritin, transferrin and iron were measured in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) and control patients. Ferritin levels were significantly elevated in the CSF of chronic progressive active MS patients (4.71+/-0.54 ng/ml) compared to levels in normal individuals (3.07+/-0.17 ng/ml). MS patients with active or stable relapsing-remitting disease had ferritin levels that were comparable to those found in normal individuals. There were no significant differences in transferrin or iron levels in the CSF between MS and normal individuals. Both ferritin and transferrin levels were elevated in patients that had high CSF IgG values but not in patients with a high IgG index. Since ferritin binds iron, the increase of CSF ferritin levels in chronic progressive MS patients could be a defense mechanism to protect against iron induced oxidative injury. Ferritin levels could be a laboratory measure that helps to distinguish between chronic progressive and relapsing-remitting MS.

Iron quantification in cerebrospinal fluid.

Several studies have attempted to measure iron levels in cerebrospinal fluid (CSF), which is believed to contain very low levels of iron. In general, the assays used in these studies suffered from poor reproducibility or lack of sensitivity. In the present study, an assay was developed that enables iron quantitation in CSF using 150 microliters of undiluted CSF, sample digestion, dot blotting, Perls' histochemistry, 3,3'-diaminobenzidine enhancement, and densitometry. Inter- and intraassay variability was low and sensitivity high (279 pg iron in 100 microliters). There were negligible readings for standard curves utilizing copper in place of iron. The iron content in eight normal CSF samples was 61.01 +/- 18.3 (SD) micrograms/liter, and in nine normal sera it was 1332.7 +/- 408.2 (SD) micrograms/liter. The present assay enables reliable measures of iron levels in biological samples. This assay should enable future studies that address how CSF iron levels change during the course of various disease states.

Relationship of the antispasticity effect of tizanidine to plasma concentration in patients with multiple sclerosis.

BACKGROUND: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an alpha 2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS. OBJECTIVE: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity. SETTING: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada. DESIGN: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg). PATIENTS: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other alpha-noradrenergic agonist, entered the trial. RESULTS: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration. CONCLUSIONS: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

Desferrioxamine in chronic progressive multiple sclerosis: a pilot study.

Chronic progressive Multiple Sclerosis is refractory to many conventional treatments. We performed a pilot study testing desferroxamine (DFO) as a candidate in the treatment of chronic progressive Multiple Sclerosis. DFO was given daily by 8 h subcutaneous infusions at a dose of 2 grams daily for 7 days, followed by 1 gram daily for 7 days. Eighteen of 19 individuals completed the full dose of 21 grams. One patient was unable to complete the course due to nausea. No acute deterioration of neurological status was seen during the administration of DFO. No worsening of vision or hearing was noted except that the one patient who was unable to tolerate the medication had a transient reduction in hearing. All patients had a local redness at the injection site. None of the patients had any sudden worsening during or shortly after the treatment. This pilot study suggests that DFO is relatively well tolerated by Multiple Sclerosis patients when given in a short course of therapy.

Multiple sclerosis.

Multiple sclerosis is a chronic disease that begins in late adolescence or adulthood. It is highly variable in its expression and severity. It is believed to be autoimmune in nature. The cause is unknown; both genetic and environmental factors have been implicated in the pathogenesis. MS generally presents with the acute or subacute onset of neurologic abnormalities that may wax and wane over many years. Diagnosis is generally made by means of observation of the clinical course in conjunction with a neurologic examination and laboratory tests. These tests may include magnetic resonance imaging of the head and spine, lumbar puncture, and evoked potentials. Treatment is based on general supportive care, the use of corticosteroids for relapses, and symptomatic management of ongoing problems. The frequency of relapses can be reduced with interferon-beta (Betaseron). Copolymer 1 and interferon-beta la are being evaluated by the U.S. Food and Drug Administration for approval for use for reduction in the frequency of relapses in relapsing-remitting MS. Treatment of chronic progression is often attempted with immunosuppressive agents such as corticosteroids, azathioprine, and cyclophosphamide. Use of other agents is being investigated.

Testing lazaroids U-74389G and U-83836E for therapeutic value in experimental allergic encephalomyelitis in the Lewis rat.

Reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) are toxic molecules that are thought to play a pathogenic role in many disease states, and data from prior studies indicate a role for ROI and RNI in the pathogenesis of experimental allergic encephalomyelitis (EAE). ROI and RNI can elicit tissue damage by initiating the chain reaction of lipid peroxidation. Lazaroids are a series of compounds that have been shown to interrupt lipid peroxidation. In the present study, the lazaroids, U-74389G and U-83836E, were administered to Lewis rats with EAE in order to evaluate their therapeutic effectiveness. Several different doses and administration routes, which were based on the manufacturer's (Upjohn) recommendations and a prior experimental study, were employed: 1) intraperitoneal injection (IP), 1mg drug/kg body weight, 1x/day from 7-18 days postencephalitogen injection (diseases onset approximately 9 day), male; 2) IP, 1mg/kg, 1x/day from 0-18 days, male; 3) intravenous (IV) cannula, 3mg/kg, 2x/day from 7-18 days, female; 4) IV cannula, 3mg/kg, 2x/day from 7-18 days, male; and 5) IV cannula, 10mg/kg, 2x/day from 7-18 days, female. The weights and clinical signs were evaluated on a daily basis. In all treatment regimens, there was an absence of a statistically significant difference between the vehicle-treated animals and the two groups of drug-treated animals. These data imply that lipid peroxidation may not be an effective therapeutic site in EAE. It is important to note that there are several different types of EAE and our study only explored the EAE model in the Lewis rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Usher's syndrome and multiple sclerosis. Review of an individual with Usher's syndrome with a multiple sclerosis-like illness.

We describe an individual with Type I Usher's syndrome and a multiple sclerosis-like illness. MRI scan showed vermian atrophy on T1-weighted images and multiple white matter lesions in the periventricular areas on T2-weighted images. Although MRIs demonstrating increased signal intensity on weighted images are reported in some individuals with Usher's syndrome, the cerebrospinal fluid findings are not described in these cases. In the present case, oligoclonal bands were present in the spinal fluid. The possibility of a linkage between the two diseases is raised.

Discordance of the T-cell receptor alpha-chain gene in familial multiple sclerosis.

We studied restriction fragment length polymorphisms of the T-cell receptor alpha-chain (TCR alpha) gene in DNA obtained from 99 individuals of 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Six normal family members had abnormal cranial MRIs. Linkage analysis utilized constructed haplotypes of EcoRV, Sst I, and Taq I polymorphisms. With penetrance values from 0.1 to 0.7, and scoring the normal individuals with abnormal MRIs as either unknown or affected, LOD scores were between -3.16 and -7.95 for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1, the LOD scores ranged from -6.77 to -23.08. These findings do not support a direct role of TCR alpha in the inheritance of MS.

Acute VIth cranial nerve dysfunction in multiple sclerosis. Evaluation by magnetic resonance imaging.

VIth nerve palsy is not frequently considered a presenting sign of multiple sclerosis (MS); however, MS has been documented as a fairly common cause of VIth nerve dysfunction. In the present study we have evaluated the clinical features and magnetic resonance imaging (MRI) findings in four MS patients with acute VIth nerve palsy. Diplopia as a result of acute VIth nerve palsy was the prominent symptom leading to the diagnosis of MS in all of the individuals. Other signs specifically localizing to the ipsilateral brainstem were absent in these patients. Cranial MRI revealed multiple white matter lesions with a periventricular predominance in all four patients and pontine white matter lesions in three of the patients. These lesions were either adjacent to the VIth nerve nucleus or involved the fasciculus of the VIth nerve or both.

Discordance of T-cell receptor beta-chain genes in familial multiple sclerosis.

Restriction fragment length polymorphisms of the T-cell receptor beta-chain gene were studied in DNA obtained from 96 individuals from 14 multiplex families with multiple sclerosis (MS). Thirty-four family members had definite MS and two had probable MS. Five normal family members had abnormal findings on cranial magnetic resonance imaging (MRI) scans. Linkage analysis was performed using the BglII and the KpnI polymorphisms. With penetrance values from 0.1 to 0.7, and altering the scoring of the normal individuals with abnormal findings on MRI scans from "unknown" to "affected," log of the odds scores between -4.59 to -12.76 were found for the autosomal dominant model. For the autosomal recessive model with a penetrance range from 0.1 to 1.0, the LOD scores ranged from -8.20 to -32.98. These findings do not support a direct role of T-cell receptor beta-chain gene in the inheritance of MS.