Luanne M. Metz

Review: Endocrine disrupting chemicals and immune responses: A focus on bisphenol-A and its potential mechanisms

Endocrine disrupting chemicals (EDCs) have become of concern for a variety f health issues. Due to their effects on the endocrine system they have been thoroughly examined with regards to sexual dysfunction, malformation, and cancers of reproductive origin. Bisphenol-A (BPA) is a widely studied EDC and has been characterized regarding its estrogenic effects on a variety of cell types. BPA also alters immune responses. In this review, we examine some of the documented effects of EDCs, with a focus on BPA that pertain to modulation of the immune system and various immune cell populations. We highlight the multiple actions of BPA on altering T cell subsets, B cell functions, and dendritic cell and macrophage biology. Finally, we consider that these immunological activities of BPA may be mediated through estrogen receptor signaling, arylhydrocarbon receptor, and the peroxisome proliferator-activated receptor family of nuclear receptors.

The promise of minocycline in neurology

The capacity of minocycline to alleviate disease for several neurological disorders in animals is increasingly being recognised. Indeed, that one drug alone can attenuate the severity of disease in stroke, multiple sclerosis, spinal-cord injury, Parkinsons disease, Huntingtons disease, and amyotrophic lateral sclerosis is astounding. In this review, we describe the evidence for the efficacy of minocycline in several animal models of neurological disease, discuss the mechanisms by which minocycline affects a range of neurological diseases with diverse causes, and introduce the emerging investigation of minocycline in clinical neurology. The encouraging results of minocycline in experimental neurology bode well for its therapeutic use in human neurological diseases.

Major depression in multiple sclerosis: a population-based perspective.

Objective: To determine the prevalence of major depression in multiple sclerosis (MS) in a population-based sample controlling for nonspecific illness effects. Methods: This study used data from a large-scale national survey conducted in Canada: the Canadian Community Health Survey (CCHS). The analysis included 115,071 CCHS subjects who were 18 years or older at the time of data collection. The CCHS interview obtained self-reported diagnoses of MS and employed a brief predictive interview for major depression: the Composite International Diagnostic Interview Short Form for Major Depression. The 12-month period prevalence of major depression was estimated in subjects with and without MS and with and without other long-term medical conditions. Results: The prevalence of major depression was elevated in persons with MS relative to those without MS and those reporting other conditions. The association persisted after adjustment for age and sex (adjusted odds ratio = 2.3, 95% CI 1.6 to 3.3). Major depression prevalence in MS for those in the 18- to 45-year age range was high at 25.7% (95% CI 15.6 to 35.7). Conclusions: The prevalence of major depression in the population with MS is elevated. This elevation is not an artifact of selection bias and exceeds that associated with having one or more other long-term conditions.

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Minocycline reduces gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis

We report a trial of minocycline in people with relapsingremitting multiple sclerosis (RRMS) that evaluates safety and estimates its effect on magnetic resonance imaging (MRI). Ten subjects with active RRMS received oral minocycline 100mg twice daily for 6 months after a 3-month run-in period. A 30-month treatment extension is ongoing. Clinical and laboratory assessments were completed at enrollment and then at 3-month intervals. MRI was performed at enrolment and then every 4 weeks. Patients without MRI activity during the run-in phase continued in the study, including completion of all MRI scans, to confirm lack of MRI worsening. The primary outcome was change in the mean number of gadolinium-enhancing lesions per scan during the first 6 months of treatment compared with the run-in period (Wilcoxon signed rank test, two-sided alpha of 0.05). Eighty percent of participants were women. Mean age was 42.8 years (SD 4.0). Mean MS duration was 11.8 years (SD 6.3). Median baseline extended disability status score (EDSS) was 2.5 (range 1.5–5.5). Mean relapse number in the two prior years was 2.6 (range 2–4). During the trial, there were no serious adverse events or laboratory abnormalities and no change in EDSS. Three relapses occurred during the run-in phase, five during the first 6-month treatment phase, and none during the following 6 months. On-treatment relapses included one associated with MRI enhancement (during month 1), two without enhancement (one scan was a postrelapse scan, and one scan was missed because the patient was taking steroids), and two mild truncal sensory attacks unassociated with MRI enhancement (both at 5 months). Mean total enhancing lesion number decreased from 1.38 lesions per scan during the run-in phase to 0.22 during the treatment phase (z 2.204, p 0.0276), representing a relative reduction of greater than 84%. During the run-in phase, 47.5% of MRI scans (19/40) were active, whereas 9.3% (5/54) were active during the minocycline phase. There were no active scans after month 2 (Fig) and no new active lesions after month 1. Although five patients accounted for all MRI activity before and after treatment, all patient data were included in all analyses. This study provides preliminary evidence that minocycline may be useful in MS and supports its safety. The MRI results are consistent with the ability of minocycline to inhibit matrix metalloproteinases, thus reducing lymphocyte access to the central nervous system. In addition, minocycline may have other beneficial properties including neuroprotection. Small sample size and short trial duration limit conclusions, but reduced MRI activity is encouraging and calls for definitive studies to establish minocycline efficacy in MS.

A comparison of health utility measures for the evaluation of multiple sclerosis treatments

Objectives: To evaluate the practical application and psychometric properties of three health utility measures in a sample of MS patients with a broad range of neurological disability as measured by the Extended Disability Status Scale (EDSS). Methods: Patients randomly selected from two MS clinic registries were assessed using standard clinical methods and completed three generic measures of health utility (EQ-5D, HUI Mark III, SF-6D). The proportion of missing data, test/retest reliability, and construct validity of each health utility measure were examined. Results: The assessments were completed by 187 patients. Less than 10% of data were missing for the subscales of the SF-6D (<3.2%), HUI Mark III (<1.6%), and EQ-5D (⩽7.5%). Severely disabled patients were more likely to omit physical function questions for the SF-6D (20%), and EQ-5D (43%). Retest reliability for the SF-6D (ICC = 0.83), EQ-5D (ICC = 0.81), and HUI Mark III (ICC = 0.87) were adequate for population surveys. Correlations between assessment of clinical function and each health utility measure were strongest for the HUI Mark III (HUI Mark III EDSS ρ = −0.77, HUI Mark III ambulation index ρ = −0.76, HUI Mark III timed 25 foot walk ρ = −0.73, HUI Mark III nine hole peg test ρ = −0.65). Conclusions: The health utility measures were generally feasible and reliable but the HUI Mark III demonstrated highest concordance with the EDSS across the full range of neurological disability. Of the three measures studied, the HUI Mark III may be the most appropriate for cost effectiveness evaluations of MS therapies.

Long-Term Medical Conditions and Major Depression: Strength of Association for Specific Conditions in the General Population

Background: The prevalence of major depression (MD) in persons with nonpsychiatric medical conditions is an indicator of clinical need in those groups, an indicator of the feasibility of screening and case-finding efforts, and a source of etiologic hypotheses. This analysis explores the prevalence of MD in the general population in relation to various long-term medical conditions. Methods: We used a dataset from a large-scale Canadian national health survey, the Canadian Community Health Survey (CCHS). The sample consisted of 115 071 subjects aged 18 years and over, randomly sampled from the Canadian population. The survey interview recorded self-reported diagnoses of various long-term medical conditions and employed a brief predictive interview for MD, the Composite International Diagnostic Interview Short Form for Major Depression. Logistic regression was used to adjust estimates of association for age and sex. Results: The conditions most strongly associated with MD were chronic fatigue syndrome (adjusted odds ratio [AOR] 7.2) and fibromyalgia (AOR 3.4). The conditions least strongly associated were hypertension (AOR 1.2), diabetes, heart disease, and thyroid disease (AOR 1.4 in each case). We found associations with various gastrointestinal, neurologic, and respiratory conditions. Conclusions: A diverse set of long-term medical conditions are associated with MD, although previous studies might have lacked power to detect some of these associations. The strength of association in prevalence data, however, varies across specific conditions.

Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population.

The objective of this paper was to evaluate the lifetime and point prevalence of major depression in a population-based Multiple Sclerosis (MS) clinic sample, and to describe associations between selected biopsychosocial variables and the prevalence of lifetime major depression in this sample. Subjects who had participated in an earlier study were re-contacted for additional data collection. Eighty-three per cent (n=136) of those eligible consented to participate. Each subject completed the Composite International Diagnostic Interview (CIDI) and an interviewer-administered questionnaire evaluating a series of biopsychosocial variables. The lifetime prevalence of major depression in this sample was 22.8%, somewhat lower than previous estimates in MS clinic populations. Women, those under 35, and those with a family history of major depression had a higher prevalence. Also, subject reporting high levels of stress and heavy ingestion of caffeine (>400 mg) had a higher prevalence of major depression. As this was a cross-sectional analysis, the direction of causal effect for the observed associations could not be determined. By identifying variables that are associated with lifetime major depression, these data generate hypotheses for future prospective studies. Such studies will be needed to further understand the etiology of depressive disorders in MS.

Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators.

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.

Regional variation of multiple sclerosis prevalence in Canada

Objective: To describe the regional distribution of multiple sclerosis (MS) prevalence in Canada, controlling for age and sex. Methods: This study used data from the Canadian Community Health Survey, a large general health survey (n=131,535) conducted in 2000/2001. Subjects aged 18 and over were included in the current analysis (n=116,109). The presence of MS was determined by self-report. Prevalence was computed in five regions (Atlantic, Quebec, Ontario, Prairies and British Columbia). Logistic regression was used to compare regions and examine for confounding/interaction by age and sex. Results: The overall Canadian MS prevalence was 240 per 100 000 (95%CI: 210-280). Prevalence ranged from 180 (95%CI: 90-260) in Quebec to 350 (95%CI: 230-470) in Atlantic Canada. Logistic regression revealed no statistical difference between the odds of MS in Quebec, Ontario and British Columbia adjusted for age and sex. The adjusted odds of MS in the Prairies and Atlantic regions were significantly higher than in the other regions combined, with odds ratios of 1.7 (95%CI: 1.1-2.4, p<0.01) and 1.6 (95%CI: 1.1-2.4, p<0.05) respectively. Sensitivity analysis demonstrated similar prevalence in the nonaboriginal/nonimmigrant group (n=96 219). Conclusion: Results suggest that Canadian MS prevalence differs by region. If validated, these regional differences may facilitate investigation of environmental influences.