Suicide mortality in relation to dietary intake of n-3 and n-6 polyunsaturated fatty acids and fish: equivocal findings from 3 large US cohort studies.

Intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs) has been implicated in the pathogenesis of depression. We sought to estimate the association between intake of fish and n-3 and n-6 PUFAs and suicide mortality over the course of long-term follow-up. In this prospective cohort study, biennial questionnaires were administered to 42,290 men enrolled in the Health Professionals Follow-up Study (1988-2008), 72,231 women enrolled in the Nurses' Health Study (1986-2008), and 90,836 women enrolled in Nurses' Health Study II (1993-2007). Dietary fish and n-3 and n-6 PUFA intakes were assessed every 4 years using a validated food-frequency questionnaire. Suicide mortality was ascertained through blind physician review of death certificates and hospital or pathology reports. Adjusted relative risks of suicide mortality were estimated with multivariable Cox proportional hazards models and pooled across cohorts using random-effects meta-analysis. The pooled multivariable relative risks for suicide among persons in the highest quartile of intake of n-3 or n-6 PUFAs, relative to the lowest quartile, ranged from 1.08 to 1.46 for n-3 PUFAs (Ptrend = 0.11-0.52) and from 0.68 to 1.19 for n-6 PUFAs (Ptrend = 0.09-0.54). We did not find evidence that intake of n-3 PUFAs or fish lowered the risk of completed suicide.

Inflammatory dietary pattern and risk of depression among women.

BACKGROUND: Inflammation is considered as a mechanism leading to depression, but the association between inflammatory dietary pattern and depression risk is unknown. METHODS: Using reduced-rank regression, we identified a dietary pattern that was related to plasma levels of inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor α receptor 2), and we conducted a prospective analysis of the relationship of this pattern and depression risk among participants in the Nurses' Health Study. A total of 43,685 women (aged 50-77) without depression at baseline (1996) were included and followed up until 2008. Diet information was obtained from food frequency questionnaires completed between 1984 through 2002 and computed as cumulative average of dietary intakes with a 2-year latency applied. We used a strict definition of depression that required both self-reported physician-diagnosed depression and use of antidepressants, and a broader definition that included women who reported either clinical diagnosis or antidepressant use. RESULTS: During the 12-year follow-up, we documented 2594 incident cases of depression using the stricter definition and 6446 using the broader definition. After adjustment for body mass index and other potential confounders, relative risks comparing extreme quintiles of the inflammatory dietary pattern were 1.41 (95% confidence interval [CI], 1.22, 1.63; P-trend<.001) for the strict definition and 1.29 (95% CI, 1.18, 1.41; P-trend<.001) for the broader definition of depression. CONCLUSIONS: The inflammatory dietary pattern is associated with a higher depression risk. This finding suggests that chronic inflammation may underlie the association between diet and depression.

Prospective study of restless legs syndrome and risk of depression in women.

Most research on the association between restless legs syndrome (RLS) and depression has involved cross-sectional data. The objective of the present study was to evaluate this issue prospectively among Nurses' Health Study participants. A total of 56,399 women (mean age = 68 years) who were free of depression symptoms at baseline (2002) were followed until 2008. Physician-diagnosed RLS was self-reported. During 300,155 person-years of follow-up, the authors identified 1,268 incident cases of clinical depression (regular use of antidepressant medication and physician-diagnosed depression). Women with RLS at baseline were more likely to develop clinical depression (multivariate-adjusted relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1; P = 0.02) than those without RLS. The presence of RLS at baseline was also associated with higher scores on the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the 15-item Geriatric Depression Scale (GDS-15) thereafter. Multivariable-adjusted mean differences were 1.00 (standard error, 0.12) for CESD-10 score and 0.47 (standard error, 0.07) for GDS-15 score between women with RLS and those without RLS (P < 0.0001). In conclusion, women with physician-diagnosed RLS had an increased risk of developing clinical depression and clinically relevant depression symptoms. Further prospective studies using refined approaches to ascertainment of RLS and depression are warranted.

Gestational vitamin D and the risk of multiple sclerosis in offspring.

OBJECTIVE: Vitamin D may have a protective role in the etiology of multiple sclerosis (MS), but the effect of gestational vitamin D on adult onset MS has not been studied. METHODS: In 2001, 35,794 mothers of participants of the Nurses' Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse daughters. We studied the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and their daughters' risk of developing MS. RESULTS: MS was diagnosed in 199 women. The relative risk of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted rate ratio (RR) of MS was 0.62 (95% confidence interval [CI], 0.40-0.95; p trend = 0.001) for nurses whose mothers consumed 2 to 3 glasses of milk per day compared with those whose mothers consumed <3 glasses per month, and 0.57 (95% CI, 0.35-0.91; p trend = 0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH)D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles, the adjusted RR was 0.59; (95% CI, 0.37-0.92; p trend = 0.002). INTERPRETATION: Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in offspring.

Relation between clinical depression risk and physical activity and time spent watching television in older women: a 10-year prospective follow-up study.

Although physical activity (PA) has been inversely associated with depressive symptoms, it is not clear whether regular PA and television watching are associated with clinical depression risk. The authors conducted a prospective analysis involving 49,821 US women from the Nurses' Health Study who were free from depressive symptoms at baseline (1996). Information on PA was obtained from validated questionnaires completed in 1992, 1994, 1996, 1998, and 2000; analyses were conducted using the cumulative average of PA (minutes/day) with a 2-year latency period applied. Participants were asked about television-watching habits in 1992. Cox proportional hazards regression models adjusted for multiple risk factors were used to estimate relative risks of clinical depression (self-reported physician-diagnosed depression or use of antidepressants). During 10 years of follow-up (1996-2006), 6,505 incident cases of depression were documented. Higher levels of PA were associated with lower depression risk. The multivariate relative risk comparing the highest level of PA (≥ 90 minutes/day) with the lowest (<10 minutes/day) was 0.80 (95% confidence interval: 0.70, 0.92; P(trend) < 0.001). In contrast, the risk of depression increased with increasing television-watching time. The multivariate relative risk comparing women who spent 21 hours/week or more watching television with those who spent 0-1 hour/week was 1.13 (95% confidence interval: 1.00, 1.27; P(trend) = 0.01). Analyses simultaneously considering PA and television watching suggested that both contributed independently to depression risk.

The role of high-risk pregnancy in childbearing tendency in Tehran.

BACKGROUND AND PURPOSE: The decreased tendency toward childbearing is considered as one of the most social issues. High-risk pregnancy problems and the fear of recurrence can reduce the desire for re-pregnancy. The purpose of this study was to determine the relationship between high-risk pregnancies in childbearing tendency. MATERIALS AND METHODS: This descriptive study was cross-sectional. The statistical population included married women aged 15-49 years with at least one previous pregnancy. 928 women with histories of low-risk and high-risk pregnancy were selected by applying a continuous sampling method. The demographic information form and childbearing desire questionnaire were used. The data were analyzed by SPSS-16 and applying descriptive statistics tests, mean and standard deviation, inferential statistics, regression, independent t-test. FINDINGS: The mean of childbearing tendency in mothers with a history of high-risk pregnancy and low-risk pregnancy were 3.25 ± 5.43 and 8.65 ± 3.96, respectively. Before modifying the intervention variables, the mean scores of childbearing desire were significantly different in mothers with a history of low-risk pregnancy and high-risk pregnancy; it was higher in mothers with a history of low-risk pregnancy (P < 0.001). After modifying the variables of the ideal number of children, the mothers' attitude toward childbearing desire, and the number of natural childbirths, stillbirths, and miscarriages. The difference was not significant (P = 0.263). CONCLUSION: Childbearing tendency was not different in women with a history of low-risk pregnancy and those with a history of high-risk pregnancy.

Diethylstilbestrol exposure in utero and depression in women.

Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses' Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995-2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects.

The incidence of mild cognitive impairment: A systematic review and data synthesis.

INTRODUCTION: Incidence estimates of mild cognitive impairment (MCI) range widely. We obtained contemporary age-specific MCI incidence rates and examined sources of heterogeneity. METHODS: We conducted a systematic review of population-based studies from the Americas, Europe, and Australia using restrictive inclusion criteria to limit heterogeneity. Incidence was examined using 5-year age categories for MCI and amnestic/nonamnestic subtypes. Data were synthesized using quantitative and qualitative descriptive analyses and quantitative meta-analyses. RESULTS: Meta-analysis estimates (95% CI) of MCI incidence per 1000 person-years were 22.5 (5.1-51.4) for ages 75-79y, 40.9 (7.7-97.5) for ages 80-84y, and 60.1 (6.7-159.0) for ages 85+y. Despite restrictive inclusion criteria, considerable heterogeneity (measured by I2) remained. Meta-analysis findings and simple descriptive statistics were consistent and supported by qualitative review. DISCUSSION: Heterogeneity in MCI incidence estimates persisted across age-specific estimates from population samples, likely reflecting differences in populations and methods. Incidence rate ranges are important to consider with summary point estimates.

Impact of high-fat diet and hypoxia on the serum levels of main vasoconstrictors in male rabbits.

Introduction: During atherosclerosis process, vasoconstriction phenomenon occurs which in turn leads to tissue hypoxia. A few studies have been performed on the combination of atherosclerosis and hypoxia as stressors that may accelerate secretion of constrictors. The aim of present study was to evaluate the effects of atherosclerosis and hypoxia on serum levels of main vasoconstrictors (epinephrine, norepinephrine and renin). Methods: In this interventional study, 32 New Zealand white rabbits were randomly divided into four groups (n = 8): normal diet (control group), normal diet exposed to hypoxia (11%, 10 days), high-fat diet (cholesterol-2%, 8 weeks), and high-fat diet with hypoxia. Later, serum levels of renin, epinephrine and norepinephrine were measured on second, 56th and 66th days. Results: High-fat diet and hypoxia caused significant increase in epinephrine and norepinephrine concentrations on days 56 and 66 compared to the control group (P < 0.05). Also, renin showed significance increase in high-fat diet and high-fat diet+ hypoxia groups compared to the control group (P < 0.05). Conclusion: Both high-fat diet and hypoxia increase renin levels in male rabbits. Furthermore, the combination of high-fat diet and hypoxia immensely increases renin levels. Both hypoxia and combined of high-fat diet and hypoxia increase norepinephrine levels. However epinephrine is only increased in the combination of high-fat diet and hypoxia. So the presence of hypoxia in combination with high-fat diet, cause accelerated and aggravated atherosclerosis.

C-reactive protein, interleukin-6, soluble tumor necrosis factor α receptor 2 and incident clinical depression.

BACKGROUND: Despite an extensive literature on the role of inflammation and depression, few studies have evaluated the association between inflammatory biomarkers and depression in a prospective manner, and results are inconclusive. METHODS: We conducted a prospective analysis of blood levels of CRP, IL-6 and TNFα-R2 in 4756 women participating in the Nurses׳ Health Study who donated blood in 1990 and were depression-free up to 1996. Participants were followed between 1996 and 2008 for reports of clinical diagnosis depression or antidepressant use. Additionally, we conducted cross-sectional analyses for CRP, IL-6 and TNFα-R2 and antidepressant use at time of blood draw. RESULTS: After adjustment for body mass index, menopause status, use of anti-inflammatory drugs and other covariates, no significant associations between CRP, IL-6 and TNFα-R2 and incident depression were observed after a follow-up of 6-18 years. However, menopause status appears to modify the association between IL-6 and depression risk. In cross-sectional analyses, TNFα-R2 was associated with antidepressant use (OR=1.96, 95% CI=1.23-3.13, P-trend=0.001), but no significant associations were found for CRP and IL-6. LIMITATIONS: Depression diagnosis was first assessed in 1996, 6 years after blood draw. However the biomarkers have high within-person correlations with measurements 4 years apart. CONCLUSIONS: Blood levels of CRP, IL-6 and TNFα-R2 were not associated with incident depression over a follow-up of 6-18 years. In cross-sectional analyses, antidepressant use may be associated with higher levels of TNFα-R2 but no associations with depression or antidepressant use were observed in the prospective analysis.

Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults.

OBJECTIVE: To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. METHODS: We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988-2008), 73,820 women in the Nurses' Health Study (NHS, 1992-2008), and 91,005 women in the NHS II (1993-2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. RESULTS: We documented 277 deaths from suicide. Compared to those consuming ≤ 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38-0.78) for those consuming 2-3 cups/day and 0.47 (0.27-0.81) for those consuming ≥ 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63-0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63-0.93) for each increment of 300 mg/day of caffeine. CONCLUSIONS: These results from three large cohorts support an association between caffeine consumption and lower risk of suicide.

Effects of intrahippocampal injection of ghrelin on spatial memory in PTZ-induced seizures in male rats.

Ghrelin (gh) is a peptide hormone that may affect learning and memory. There is some evidence that ghrelin can have antiepileptic effects. So we decided to investigate the possible effects of ghrelin on spatial memory following PTZ-induced seizures in male rats. Ninety male rats were divided into 9 groups including control, saline, ghrelin (0.3, 1.5 or 3 nmol) and pentylenetetrazol (PTZ, 50 mg/kg, i.p.) plus saline or ghrelin (0.3, 1.5 or 3 nmol). All groups were trained in Morris water maze (MWM) for two consecutive days. Our results showed that ghrelin significantly improves spatial memory at the doses of 1.5 or 3 nmol (P<0.05) in normal rats. We also demonstrated the significant impairment of spatial memory in PTZ group (P<0.05). Intrahippocampal injection of ghrelin at the dose of 3 nmol significantly improved spatial memory in PTZ+gh group compared to PTZ group (P<0.05). These findings suggest that ghrelin as a neuropeptide can improve spatial memory in PTZ-treated rats.

Cigarette smoking and completed suicide: results from 3 prospective cohorts of American adults.

BACKGROUND: Prior reports have indicated a potential dose-response relationship between smoking and suicide. However, this relationship is controversial. METHODS: This study evaluated the association between smoking and risk of death from suicide in three large-scale cohorts of U.S. men and women (n=253,033). Suicides were identified from death certificates among 43,816 men enrolled in the Health Professionals Follow-up Study (HPFS) between 1986 and 2008, 116,566 women in the Nurses' Health Study (NHS) between 1976 and 2008, and 92,651 women in the NHS II between 1989 and 2007. Information on smoking was obtained at baseline and updated every 2 years. Relative risks (RRs) of suicide were estimated using Cox proportional hazards regression models. Cohort specific RRs were pooled using random-effects models. Suicide deaths were determined by physician review of death certificates. RESULTS: A total of 457 deaths from suicide were documented. Compared to never smokers, the pooled multivariate RR (95% confidence interval [CI]) of suicide was 1.15 (0.91-1.45) for former smokers and 2.69 (2.11-3.42) for current smokers. A nonmonotonic dose-response relationship was noted between the number of cigarettes smoked per day (CPD) and suicide risk (P trend<0.001). Compared to never smokers, the pooled multivariate RR (95% CI) was 2.59 (1.77-3.79) for those with 1-14 CPD, 2.03 (1.39-2.94) for those with 15-24 CPD, and 4.13 (2.96-5.78) for those with ≥ 25 CPD. LIMITATIONS: Smoking was self-reported and had some degree of measurement error. Participants were not a representative sample of the U.S. population. CONCLUSIONS: Results from three large cohorts suggest a nonmonotonic dose-response association between smoking and suicide risk.

Prospective study on long-term dietary patterns and incident depression in middle-aged and older women.

BACKGROUND: Although individual nutrients have been investigated in relation to depression risk, little is known about the overall role of diet in depression. OBJECTIVE: We examined whether long-term dietary patterns derived from a food-frequency questionnaire (FFQ) predict the development of depression in middle-aged and older women. DESIGN: We conducted a prospective study in 50,605 participants (age range: 50-77 y) without depression in the Nurses' Health Study at baseline (1996) who were followed until 2008. Long-term diet was assessed by using FFQs every 4 y since 1986. Prudent (high in vegetables) and Western (high in meats) patterns were identified by using a principal component analysis. We used 2 definitions for clinical depression as follows: a strict definition that required both a reported clinical diagnosis and use of antidepressants (3002 incident cases) and a broad definition that further included women who reported either a clinical diagnosis or antidepressant use (7413 incident cases). RESULTS: After adjustment for age, body mass index, and other potential confounders, no significant association was shown between the diet patterns and depression risk under the strict definition. Under the broad definition, women with the highest scores for the Western pattern had 15% higher risk of depression (95% CI: 1.04, 1.27; P-trend = 0.01) than did women with the lowest scores, but after additional adjustment for psychological scores at baseline, results were no longer significant (RR: 1.09; 95% CI: 0.99, 1.21; P-trend = 0.08). CONCLUSION: Overall, results of this large prospective study do not support a clear association between dietary patterns from factor analysis and depression risk.

Amlodipine treatment decreases plasma and carotid artery tissue levels of endothelin-1 in atherosclerotic rabbits.

Alteration in transferring of calcium ions are seen in atherosclerotic cells and amlodipine can positively influence risk factors associated with atherosclerosis, but all mechanisms are not known. Recent studies indicate that endothelin-1 (ET-1) contributes to the atheroma formation and progression of atherosclerosis. In this study, we have evaluated the effects of amlodipine treatment and/or high-cholesterol diet on blood and carotid artery tissue concentration of ET-1 in the atherosclerotic rabbits. Thirty six male New Zealand white rabbits were randomly divided into four groups: normal-diet control (NC), normal-diet receiving amlodipine (NA), high-cholesterol diet (HC) and high-cholesterol diet receiving amlodipine (HA) groups. After 8 weeks all animals were anesthetized and blood or carotid tissue samples were colleted. Eight weeks of amlodipine treatment reduced significantly total cholesterol, LDL and TG in hypercholesterolemic (HA) group. Significant increase in plasma HDL-C and decrease in TG were the main effects of amlodipine treatment on serum lipid profiles in the control group. The plasma and carotid tissue levels of ET-1 in HC group were significantly increased as compared with the NC group (p<0.01). Amlodipine treatment significantly reduced ET-1 level in NA and HA rabbits (p<0.01). Furthermore, high-cholesterol diet induced atherosclerotic lesions as shown by the enhancement of endothelial cell diameter and accumulation of lipid droplets under endothelial cells. Amlodipine treatment reduced atherotic lesions in these rabbits. Amlodipine treatment reduced levels of total cholesterol, LDL and TG as well as plasma and carotid tissue levels of ET-1 in high lipid situation. We suggest that amlodipine treatment by reducing the ET-1 may contribute to reducing the progression of atherosclerotic disease.

Coffee, caffeine, and risk of depression among women.

BACKGROUND: Caffeine is the world's most widely used central nervous system stimulant, with approximately 80% consumed in the form of coffee. However, studies that analyze prospectively the relationship between coffee or caffeine consumption and depression risk are scarce. METHODS: A total of 50,739 US women (mean age, 63 years) free of depressive symptoms at baseline (in 1996) were prospectively followed up through June 1, 2006. Consumption of caffeine was measured from validated questionnaires completed from May 1, 1980, through April 1, 2004, and computed as cumulative mean consumption with a 2-year latency period applied. Clinical depression was defined as self-reported physician-diagnosed depression and antidepressant use. Relative risks of clinical depression were estimated using Cox proportional hazards regression models. RESULTS: During 10 years of follow-up (1996-2006), 2607 incident cases of depression were identified. Compared with women consuming 1 or less cup of caffeinated coffee per week, the multivariate relative risk of depression was 0.85 (95% confidence interval, 0.75-0.95) for those consuming 2 to 3 cups per day and 0.80 (0.64-0.99; P for trend<.001) for those consuming 4 cups per day or more. Multivariate relative risk of depression was 0.80 (95% confidence interval, 0.68-0.95; P for trend=.02) for women in the highest (≥550 mg/d) vs lowest (<100 mg/d) of the 5 caffeine consumption categories. Decaffeinated coffee was not associated with depression risk. CONCLUSIONS: In this large longitudinal study, we found that depression risk decreases with increasing caffeinated coffee consumption. Further investigations are needed to confirm this finding and to determine whether usual caffeinated coffee consumption can contribute to depression prevention.

Dietary intake of n-3 and n-6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study.

BACKGROUND: The associations between different sources of dietary n-3 (omega-3) and n-6 (omega-6) fatty acids and the risk of depression have not been prospectively studied. OBJECTIVE: The objective was to examine the relation between different n-3 and n-6 types with clinical depression incidence. DESIGN: We prospectively studied 54,632 US women from the Nurses' Health Study who were 50-77 y of age and free from depressive symptoms at baseline. Information on diet was obtained from validated food-frequency questionnaires. Clinical depression was defined as reporting both physician-diagnosed depression and regular antidepressant medication use. RESULTS: During 10 y of follow-up (1996-2006), 2823 incident cases of depression were documented. Intake of long-chain n-3 fatty acids from fish was not associated with depression risk [relative risk (RR) for 0.3-g/d increment: 0.99; 95% CI: 0.88, 1.10], whereas α-linolenic acid (ALA) intake was inversely associated with depression risk (multivariate RR for 0.5-g/d increment: 0.82; 95% CI: 0.71, 0.94). The inverse association between ALA and depression was stronger in women with low linoleic acid (LA) intake (P for interaction = 0.02): a 0.5-g/d increment in ALA was inversely associated with depression in the first, second, and third LA quintiles [RR (95% CI): 0.57 (0.37, 0.87), 0.62 (0.41, 0.93), and 0.68 (0.47, 0.96), respectively] but not in the fourth and fifth quintiles. CONCLUSIONS: The results of this large longitudinal study do not support a protective effect of long-chain n-3 from fish on depression risk. Although these data support the hypothesis that higher ALA and lower LA intakes reduce depression risk, this relation warrants further investigation.

Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis.

OBJECTIVE: To characterize the association between infectious mononucleosis (IM), a frequent clinical manifestation of primary Epstein-Barr virus infection after childhood, and the risk for multiple sclerosis (MS). METHODS: We conducted a systematic review and meta-analysis of case-control and cohort studies of IM and MS. RESULTS: The combined relative risk of MS after IM from 14 studies was 2.3 (95% confidence interval, 1.7-3.0; p < 10(-8)). Potential sources of heterogeneity (ie, study design, MS definition, and latitude) barely influenced our results. INTERPRETATION: We conclude that Epstein-Barr virus infection manifesting as IM in adolescents and young adults is a risk factor for MS.