Incidence of multiple sclerosis in the United Kingdom : findings from a population-based cohort.

Existing data on the incidence of multiple sclerosis (MS) in the UK have some limitations. Few studies have reported age- and sex-specific incidence rates of MS, and none of those is based on a large sample of the general population. Further, no published reports have provided age- and sex-specific incidence rates of MS by clinical course from onset. To estimate the age- and sex-specific incidence rate and lifetime risk of multiple sclerosis, we identified all new cases of MS during the period 1993-2000 in the General Practice Research Database, which includes health information on over three million Britons. Based on 642 incident cases, incidence rates of MS adjusted to the world population were 7.2 (95 % CI 6.5, 7.8) in women and 3.1 (95 % CI 2.6, 3.5) in men. The incidence of MS with relapsing-remitting onset was higher in women than in men (incidence rate ratio 2.5, 95% CI 2.1, 3.1), but there were no sex differences for primary-progressive MS (incidence rate ratio 1.1, 95% CI 0.7, 1.8). The estimated lifetime risk from birth of receiving an MS diagnosis was 5.3 per 1,000 in women and 2.3 per 1,000 in men. These results confirm the relatively high incidence of MS in the UK and show marked differences in the sex-specific pattern of MS incidence by clinical course from onset.

Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis: a longitudinal study.

OBJECTIVE: To investigate the relationship between magnetic resonance imaging regional lesion burden and cognitive performance in multiple sclerosis (MS) over a 4-year follow-up period. DESIGN: Twenty-eight patients with MS underwent magnetic resonance imaging and took the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis at baseline, 1-year, and 4-year follow-up. An automated 3-dimensional lesion detection method was used to identify MS lesions within anatomical regions on proton density T2-weighted images. The relationship between magnetic resonance imaging regional lesion volumes and the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis results was examined using regression analyses. RESULTS: At all time points, frontal lesion volume represented the greatest proportion of total lesion volume, and the percentage of white matter classified as lesion was also highest in frontal and parietal regions. On neuropsychological testing, when compared with age- and educational level-matched control subjects, patients with MS showed significant impairment on tests of sustained attention, processing speed, and verbal memory (P<.001). Performance on these measures was negatively correlated with MS lesion volume in frontal and parietal regions at baseline, 1-year, and 4-year follow-up (R = -0.55 to -0.73, P<.001). CONCLUSIONS: Multiple sclerosis lesions show a propensity for frontal and parietal white matter. Lesion burden in these areas was strongly associated with performance on tasks requiring sustained complex attention and working verbal memory. This relationship was consistent over a 4-year period, suggesting that disruption of frontoparietal subcortical networks may underlie the pattern of neuropsychological impairment seen in many patients with MS.

Geographic variation of MS incidence in two prospective studies of US women.

OBJECTIVE: To estimate the incidence of MS and its relation to latitude in two ongoing prospective studies of US women. BACKGROUND: A higher incidence of MS has been found in northern areas compared with southern areas of the United States and other countries, but the attenuation of this gradient in Europe in the last few decades and the consideration of ethnic factors have led some authors to question the existence of a strong association between MS and latitude. METHODS: The authors identified new cases of MS among participants in the Nurses' Health Study (NHS), which took place between 1976 and 1994, and in the Nurses' Health Study II (NHS II), which took place between 1989 and 1995. The NHS included women born between 1920 and 1946, and the NHS II included women born between 1947 and 1964. RESULTS: The incidence of MS among NHS participants (181 definite/probable patients) increased significantly with latitude (p = 0.03, trend). Adjusted rate ratios were 3.5 (95% CI, 1.1, 11.3) for the north and 2.7 (95% CI, 0.8, 8.9) for the middle tiers relative to the southern tier. Among NHS II women (131 definite/probable patients), no association between latitude and MS was found (p = 0.89, trend). Adjusted rate ratios were 0.8 (95% CI, 0.4, 1.6) for the northern areas and 0.9 (95%, 0.4, 1.8) for the middle areas, relative to the southern areas. CONCLUSION: The association between latitude and risk of MS in the United States was corroborated, but there was an attenuation of the north-south gradient over time. If confirmed, this finding could provide new clues to identifying environmental causes of the disease.

Intakes of carotenoids, vitamin C, and vitamin E and MS risk among two large cohorts of women.

BACKGROUND: Antioxidant nutrients may reduce the risk of MS. In a recent case-control study, vitamin C intake was significantly inversely associated with MS risk among women. However, no prospective data are available. OBJECTIVE: To examine prospectively the associations of intakes of carotenoids, vitamin C, and vitamin E with the risk of MS among women. METHODS: The authors documented the occurrence of definite and probable MS within two large cohorts of women who completed detailed and validated semiquantitative food frequency questionnaires. One cohort (Nurses' Health Study) comprised 81,683 women aged 38 to 63 years in 1984, who were followed for 12 years; the other (Nurses' Health Study II) comprised 95,056 women aged 27 to 44 years in 1991, who were followed for 6 years. RESULTS: The authors documented a total of 214 cases of MS. After adjustments for age, latitude of birthplace, pack-years of smoking, and total energy intake, the pooled multivariate relative risks (95% CIs) comparing women in the highest quintile with those in the lowest quintile were 1.1 (0.7 to 1.7) for alpha-carotene, 1.1 (0.7 to 1.6) for beta-carotene, 1.4 (0.8 to 2.2) for beta-cryptoxanthin, 1.0 (0.6 to 1.5) for lycopene, 1.0 (0.7 to 1.6) for lutein/zeaxanthin, 1.4 (0.9 to 2.1) for total vitamin C, 1.3 (0.9 to 2.0) for dietary vitamin C, 0.8 (0.6 to 1.3) for total vitamin E, and 0.9 (0.6 to 1.4) for dietary vitamin E. The authors found no associations between intakes of fruits and vegetables and risk of MS. Use of vitamin C, vitamin E, and multivitamin supplements was also unrelated to risk of MS. CONCLUSIONS: These findings do not support hypotheses relating higher intakes of dietary carotenoids, vitamin C, and vitamin E to reduced risk of MS in women.

Oral contraceptives and the incidence of multiple sclerosis.

BACKGROUND: Experimental and clinical data suggest a protective effect of estrogens on the development and progression of MS. METHODS: We assessed whether MS incidence was associated with oral contraceptive use or parity in two cohort studies of U.S. women, the Nurses' Health Study (NHS; 121,700 women aged 30 to 55 years at baseline in 1976) and the Nurses' Health Study II (NHS II; 116,671 women aged 25 to 42 years at baseline in 1989). Participants with a diagnosis of MS before baseline were excluded. Oral contraceptive history and parity were assessed at baseline and updated biennially. During follow-ups of 18 years (NHS) and 8 years (NHS II) we documented a total of 315 definite or probable cases of MS. RESULTS: Neither use of oral contraceptives nor parity were significantly associated with the risk of MS. As compared with women who never used oral contraceptives, the age-adjusted relative risk (95% CI) was 1.2 (0.9, 1.5) for past users, and 1.0 (0.6, 1.7) for current users. Similar results were obtained after adjustment for latitude, ancestry, and other potential confounding factors. There was no clear trend of MS risk with either increasing duration of use or time elapsed since last use. Age at first birth was also not associated with the risk of MS. CONCLUSIONS: These prospective results do not support a lasting protective effect of oral contraceptive use or pregnancy on the risk of MS. The decision to use hormonal contraception should not be affected by its effects on the risk of MS.

Multiple sclerosis--Part 2. Treatment strategies.

Because it is a chronic, relapsing or progressive disease, multiple sclerosis has an unpredictable clinical course generally spanning 10 to 20 years. During that time, neurologic disability is cumulative. Therefore, it is difficult to evaluate the efficacy of a given mode of treatment in an individual patient. This second part of a two-part series reviews current and emerging modes of therapy for multiple sclerosis. Future treatment directions in multiple sclerosis will require a better understanding of the pathophysiology of the disease. Future therapeutic modalities will also rely on more accurate clinical markers, such as improved magnetic resonance imaging techniques or specific immune markers to follow the disease progression. Part 1 of this series appearing in the November 1999 issue of JAOA included several sections on multiple sclerosis, including an overview, pathophysiology, diagnostic evaluation, and clinical parameters.

Multiple sclerosis--Part I. Overview, pathophysiology, diagnostic evaluation, and clinical parameters.

A review article on multiple sclerosis (MS) is difficult because the pace of current research in the evaluation and treatment of the disease has accelerated greatly in the past 5 years. The rapidly expanding field of immunology together with the plethora of new drug trials makes the task of including all relevant material impossible. This first of a two-part article will include several sections on MS, including an overview, pathophysiology, diagnostic evaluation, and clinical parameters. The second part, to appear in the December issue, will look at treatment strategies and future directions.

Charcot-Marie-Tooth disease type I diagnosed in a 5-year-old boy after vincristine neurotoxicity, resulting in maternal diagnosis.

Charcot-Marie-Tooth disease type 1, also known as hereditary motor sensory neuropathy type 1, is an uncommon autosomal dominant disease that causes destruction of peripheral nerves with a varied clinical course, but often leads to muscle weakness. If the peroneal muscle is involved, the patient may develop a characteristic slapping gait. The dose-limiting side effect of the chemotherapeutic agent vincristine is usually its neurotoxicity. We report the case of a 5-year-old patient with leukemia who developed an acute polyneuropathy after treatment with vincristine. Charcot-Marie-Tooth disease type 1 was diagnosed in the patient and, subsequently, in his mother only after vincristine toxicity was observed.

Clinically meaningful changes in health-related quality of life in patients diagnosed with hepatobiliary carcinoma.

BACKGROUND: To test the reliability, sensitivity to change in biomarkers associated with disease progression and response to treatment, and clinical meaningfulness of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) in patients with hepatobiliary carcinoma. PATIENTS AND METHODS: One hundred and fifty-eight patients diagnosed with hepatobiliary carcinoma were prospectively studied. Health-related quality of life (HRQL) was assessed at baseline (prior to treatment), 3-month follow-up (n=55) and 6-month follow-up (n=27). RESULTS: The internal consistency of all the scales of the FACT-Hep were adequate at all time points (>0.75). The FACT-Hep was found to be sensitive to changes in clinical indicators (alkaline phosphate, alpha-fetoprotein, hemoglobin and survival) that reflect disease progression and response to treatment. Combined results from distribution-based and cross-sectional anchor-based analyses provide the following minimally important difference (MID) estimates: FACT-General (FACT-G) subscales=2-3; FACT-G=6-7; Hepatobiliary Cancer Subscale=5-6; FACT-Hep=8-9; Trial Outcome Index=7-8; and FACT-Hepatobiliary Symptom Index=2-3 points. CONCLUSIONS: The FACT-Hep is a reliable instrument that is responsive to clinical indicators of disease progression and response to treatment. The MID estimates can aid interpretation of HRQL data and facilitate sample size calculation in clinical trials.

Highly ordered MWNT-based matrixes: topography at the nanoscale conceived for tissue engineering.

A method based on the conventional lithographic technique combined with the layer-by-layer (LBL) assembly process is applied to the construction of free-standing micro- and nanostructured matrixes. The method enables controlled shaping and considerable chemical and mechanical stability of the self-assembled monolayers, allowing for high reproducibility in manufacturing. The matrixes are characterized by controlled geometry, surface topography, and chemical composition. The complete architecture is made up of successive layers of intercrossed carbon nanotubes that self-assemble into orderly structures. In particular, the present method aims to create architectures and topographies that mimic those occurring naturally (native tissue structures). In addition, nanoindentation and nanoscratch techniques were used to evaluate the mechanical properties of the carbon nanotube-based matrixes.

Nanomechanical properties of silica-coated multiwall carbon nanotubes-poly(methyl methacrylate) composites.

The mechanical properties of polymer composites, reinforced with silica-coated multiwall carbon nanotubes (MWNTs), have been studied using the nanoindentation technique. The hardness and the Young's modulus have been found to increase strongly with the increasing content of these nanotubes in the polymer matrix. Similar experiments conducted on thin films containing MWNTs, but without a silica shell, revealed that the presence of these nanotubes does not affect the nanomechanical properties of the composites. While carbon nanotubes (CNTs) have a very high tensile strength due to the nanotube stiffness, composites fabricated with CNTs may exhibit inferior toughness. The silica shell on the surface of a nanotube enhances its stiffness and rigidity. Our composites, at 4 wt % of the silica-coated MWNTs, display a maximum hardness of 120 +/- 20 MPa, and a Young's modulus of 9 +/- 1 GPa. These are respectively 2 and 3 times higher than those for the polymeric matrix. Here, we describe a method for the silica coating of MWNTs. This is a simple and efficient technique, adaptable to large-scale production, and might lead to new advanced polymer based materials, with very high axial and bending strength.

A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta.

OBJECTIVE: To evaluate the efficacy and safety of combination therapy with pulse cyclophosphamide given with methylprednisolone (MP) and interferon beta (IFNbeta)-Ia in multiple sclerosis (MS) patients with active disease during IFNbeta monotherapy. METHODS: This was a randomized, single-blind, parallel-group, multicenter trial in MS patients with a history of active disease during IFNbeta treatment. Patients were randomized to either cyclophosphamide 800 mg/m2 plus methylprednisolone 1 g IV (CY/MP) or methylprednisolone once a month for six months and then followed for an additional 18 months. All patients received three days of methylprednisolone 1 g IV at screening and 30 mcg IFNbeta-Ia IM weekly for the entire 24 months. The primary endpoint was change from baseline in the mean number of gadolinium-enhancing (Gd+) lesions. Secondary clinical endpoints included time to treatment failure. RESULTS: Fifty-nine patients were randomized to treatment: 30 to CY/MP and 29 to MP Change from baseline in the number of Gd+ lesions was significantly different between treatment groups at three (P =0.01), six (P =0.04) and 12 months (P =0.02), with fewer lesions in the CY/MP group. The cumulative rate of treatment failure was significantly lower in the CY/MP group compared with the MP group (rate ratio =0.30; 95% confidence interval, 0.12-0.75; P =0.011). CY/MP treatment was well tolerated. CONCLUSION: Combination therapy with CY/MP and IFNbeta-Ia decreased the number of Gd+ lesions and slowed clinical activity in patients with previously active disease on IFNbeta alone.

[Application of electrochemical detection to the analysis of some residues of carbamate insecticides by high performance liquid chromatography]. / Application de la détection électrochimique au dosage des résidus de quelques insecticides carbamates par chromatographie liquide haute performance.

A new high-performance liquid chromatographic determination of residues of some carbamate insecticides with electrochemical detection after degradation of molecules as the phenols is described. Residues of carbamate insecticides in vegetables can be quantified with high sensitivity.

Cigarette smoking and incidence of multiple sclerosis.

Experimental data suggest that cigarette smoking may play a role in the development of multiple sclerosis (MS), but epidemiologic studies have been small and inconclusive. The authors assessed the association between MS incidence and smoking in two cohort studies of US women, the Nurses' Health Study (121,700 women aged 30-55 years at baseline in 1976) and the Nurses' Health Study II (116,671 women aged 25-42 years at baseline in 1989). Smoking history was assessed at baseline and updated on biennial questionnaires. A total of 315 definite or probable cases of MS were documented. Compared with that for women who never smoked, the relative incidence rate was 1.6 (95% confidence interval: 1.2, 2.1) among current smokers and 1.2 (95% confidence interval: 0.9, 1.6) among past smokers after adjustment for age, latitude, and ancestry. The relative rate increased significantly with cumulative exposure to smoking (p for trend < 0.05), from 1.1 (95% confidence interval: 0.8, 1.6) for 1-9 pack-years to 1.5 (95% confidence interval: 1.2, 2.1) for 10-24 pack-years and 1.7 (95% confidence interval: 1.2, 2.4) for 25 or more pack-years. Similar results were obtained after adjustment for other potential confounding factors. Although these prospective results do not prove a cause-and-effect relation, they suggest that smoking is associated with an increased risk of MS.

Dietary fat in relation to risk of multiple sclerosis among two large cohorts of women.

Ecologic correlations suggest that higher intake of saturated fat and lower intake of polyunsaturated fat might increase the risk of multiple sclerosis (MS), but the results of case-control studies have been inconsistent. Because no prospective data are available, the authors examined these associations in two large cohorts, the Nurses' Health Study, which consisted of 92,422 women with 14 years of follow-up (1980-1994) and the Nurses' Health Study II, which consisted of 95,389 women with 4 years of follow-up (1991-1995). They documented 195 new cases of MS. The pooled multivariate relative risks comparing women in the highest quintile with those in the lowest were 1.1 (95% confidence interval: 0.7, 1.7) for total fat, 0.7 (95% confidence interval: 0.5, 1.2) for animal fat, 1.2 (95% confidence interval: 0.7, 2.1) for vegetable fat, 0.8 (95% confidence interval: 0.5, 1.3) for saturated fat, 1.1 (95% confidence interval: 0.7, 1.7) for monounsaturated fat, 1.7 (95% confidence interval 1.0, 2.8) for n-6 polyunsaturated fat, 1.3 (95% confidence interval: 0.8, 2.0) for trans unsaturated fat, and 0.7 (95% confidence interval: 0.4, 1.1) for cholesterol. Omega-3 fatty acids from fish were also unrelated to risk. However, the authors observed a nonsignificantly lower risk of MS for a higher intake of linolenic acid. These findings do not support relations between intakes of total fat or major specific types of fat and the risk of MS.

Multiple sclerosis and age at infection with common viruses.

Increased risk of multiple sclerosis has been reported among individuals with a history of measles and other common childhood diseases during adolescence, infectious mononucleosis, or exposure to the canine distemper virus. We investigated these associations in a case-control study nested within the Nurses' Health Study (121,700 women traced since 1976) and the Nurses' Health Study II (116,671 women traced since 1989). Age at diagnosis of common viral diseases and birth order were obtained through a questionnaire. Our results include 301 cases with multiple sclerosis and their (up to six) matched controls. Except for infectious mononucleosis, which was a moderate risk factor (odds ratio = 2.1, 95% confidence interval = 1.5-2.9), we found little association between history of common viral diseases or exposure to canine distemper virus and risk of multiple sclerosis. We did find a relation between mumps after 15 years of age (odds ratio = 2.3, 95% confidence interval = 1.2-4.3) or measles after age 15 years of age (odds ratio = 2.8, 95% confidence interval = 0.8-9.1) and multiple sclerosis. Birth order was not materially related to multiple sclerosis. Our findings support the hypothesis that individuals who suffered from infectious mononucleosis, a marker of late infection with the Epstein-Barr virus, have an increased risk of multiple sclerosis. Late infection with other common viruses may also be associated with increased risk.

Seasonal variation of interferon-gamma production in progressive multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. There is increased interferon (IFN)-gamma secretion in MS patients in vitro, and IFN-gamma administration induces exacerbations of disease suggesting a link between IFN-gamma and disease activity. We observed significantly increased IFN-gamma production in the autumn and winter months compared with the spring and summer months in chronic progressive MS, and this increase was linked to endogenous interleukin (IL)-12 production. Increased seasonal IFN-gamma was not observed in normal control subjects, and there were no seasonal changes in IL-10 in progressive MS. These results suggest a potential environmental link between dysregulated IFN-gamma production and MS disease progression and pathogenesis.