human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: A group of young patients having multiple sclerosis was treated with dietary supplements containing calcium , magnesium and vitamin D for a period of one to two years . The experimental design employed self-pairing : the response of each patient was compared with his/her own case history as control . The number of exacerbations observed during the program was less than one half the number expected from case histories . No side effects were apparent . The dietary regimen may offer a new means of controlling the exacerbation rate in MS , at least for younger patients . The results tend to support a theory of MS which states that calcium and magnesium are important in the development , structure and stability of myelin Background A poor vitamin D status has been associated with a high disease activity of multiple sclerosis ( MS ) . Recently , we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS ( RRMS ) patients . In the present study , we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures . Methodology /Principal Findings Fifteen RRMS patients were supplemented with 20 000 IU/d vitamin D3 for 12 weeks . Vitamin D and calcium metabolism were carefully monitored , and T cell characteristics were studied by flowcytometry . All patients finished the protocol without side-effects , hypercalcaemia , or hypercalciuria . The median vitamin D status increased from 50 nmol/L ( 31–175 ) at week 0 to 380 nmol/L ( 151–535 ) at week 12 ( P<0.001 ) . During the study , 1 patient experienced an exacerbation of MS and was censored from the T cell analysis . The proportions of ( naïve and memory ) CD4 + Tregs remained unaffected . Although Treg suppressive function improved in several subjects , this effect was not significant in the total cohort ( P = 0.143 ) . An increased proportion of IL-10 + CD4 + T cells was found after supplementation ( P = 0.021 ) . Additionally , a decrease of the ratio between IFN-γ+ and IL-4 + CD4 + T cells was observed ( P = 0.035 ) . Conclusion / Significance Twelve week supplementation of high  dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism . The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator , and may be used as outcome measure for upcoming r and omized placebo-controlled trials . Trial Registration Clinical trials.gov Objective : To determine whether interferon-β ( IFN-β ) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk . Methods : In a prospect i ve cohort of 178 persons with clinical ly definite multiple sclerosis ( MS ) living in southern Tasmania in 2002–2005 ,  serum 25-hydroxyvitamin D [ 25(OH)D ] was measured biannually , with assessment by question naire for relevant factors , including IFN-β treatment . Results : Subjects reporting IFN-β use had significantly higher mean 25(OH)D than persons who did not ( p < 0.001 ) . This was mediated by an interaction between personal sun exposure and IFN-β , with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy . The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-β therapy ( p = 0.82 ) . 25(OH)D was associated with a reduced relapse risk only among persons on IFN-β ( p < 0.001 ) . Importantly , IFN-β was only protective against relapse among persons with higher 25(OH)D ( hazard ratio [ HR ] 0.58 [ 95 % confidence interval ( CI ) 0.35–0.98 ] ) , while among 25(OH)D-insufficient persons , IFN-β  increased relapse risk ( HR 2.01 [ 95 % CI 1.22–3.32 ] ) . Conclusion : In this study , we found that IFN-β therapy is associated with greater production of vitamin D from sun exposure , suggesting part of the therapeutic effects of IFN-β on relapse in MS may be through modulation of vitamin D metabolism . These findings suggest persons being treated with IFN-β should have vitamin D status monitored and maintained in the sufficiency range . Classification of evidence : This study provided Class III evidence that IFN-β is associated with reduced risk of relapse , and this effect may be modified by a positive effect of IFN-β on serum 25(OH)D levels Background Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults . Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D , mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse . We here present the protocol of an interventional clinical phase II study to test the hypothesis , that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects . Methods / Design The EVIDIMS trial is a German multi-center , stratified , r and omized , controlled and double-blind clinical phase II pilot study . Eighty patients with the diagnosis of definite multiple sclerosis or clinical ly isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be r and omized to additionally receive either high-dose ( average daily dose 10.200 IU ) or low-dose ( average daily dose 200 IU ) cholecalciferol for a total period of 18 months . The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla . Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration , clinical parameters for disease activity , as well as cognition , fatigue , depression , and quality of life . Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters . Discussion In light of the discrepancy between existing epidemiological and pre clinical data on the one h and and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients . The study design presented here fulfills the criteria of a high- quality clinical phase II trial in MS.Trial Registration Clinical Trials.gov Identifier : CONTEXT Epidemiological and experimental evidence suggests that high levels of vitamin D , a potent immunomodulator , may decrease the risk of  multiple sclerosis .  There are no prospect i ve studies addressing this hypothesis . OBJECTIVE To examine whether levels of 25-hydroxyvitamin D  are associated with risk of multiple sclerosis . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study among more than 7 million US military personnel who have serum sample s stored in the Department of Defense Serum Repository . Multiple sclerosis cases were identified through Army and Navy physical disability data bases for 1992 through 2004 , and diagnoses were confirmed by medical record review . Each case ( n = 257 ) was matched to 2 controls by age , sex , race/ethnicity , and date s of blood collection . Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum sample s collected before the date of initial multiple sclerosis symptoms . MAIN OUTCOME MEASURES Odds ratios of multiple sclerosis associated with continuous or categorical levels ( quantiles or a priori-defined categories ) of serum 25-hydroxyvitamin D within each racial/ethnic group . RESULTS Among whites ( 148 cases , 296 controls ) , the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D ( odds ratio [ OR ] for a 50-nmol/L increase in 25-hydroxyvitamin D , 0.59 ; 95 % confidence interval , 0.36 - 0.97 ) . In categorical analyses using the lowest quintile ( < 63.3 nmol/L ) as the reference , the ORs for each subsequent quintile were 0.57 , 0.57 , 0.74 , and 0.38 ( P = .02 for trend across quintiles ) . Only the OR for the highest quintile , corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L , was significantly different from 1.00 ( OR , 0.38 ; 95 % confidence interval , 0.19 - 0.75 ; P = .006 ) . The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years . Among blacks and Hispanics ( 109 cases , 218 controls ) , who had lower 25-hydroxyvitamin D levels than whites , no significant associations between vitamin D and multiple sclerosis risk were found . CONCLUSION The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis OBJECTIVE To determine whether low levels of 25-hydroxyvitamin D ( 25[OH]D ) contribute to the increased risk of postpartum multiple sclerosis ( MS ) relapses . DESIGN Prospect i ve cohort study . SETTING Out patients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics . PATIENTS Twenty-eight pregnant women with MS . INTERVENTIONS We prospect ively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews .  Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2 , 4 , and 6 months after giving birth . The data were analyzed using longitudinal multivariable methods . MAIN OUTCOME MEASURES Levels of 25(OH)D and relapse rate . RESULTS Fourteen ( 50 % ) women breastfed exclusively , and 12 women ( 43 % ) relapsed within 6 months after giving birth . During pregnancy , the average 25(OH)D levels were 25.4 ng/mL ( range , 13.7 - 42.6 ) and were affected only by season ( P=.009 ) . In contrast , in the postpartum period , 25(OH)D levels were significantly affected by breastfeeding and relapse status . Levels of 25(OH)D remained low in the exclusive breastfeeding group , yet rose significantly in the nonexclusive breastfeeding group regardless of season ( P=.007 , unadjusted ; P=.02 , adjusted for season ) . By 4 and 6 months after childbirth , 25(OH)D levels were , on average , 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group ( P=.001 ) . CONCLUSIONS Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels  in women with MS . However , these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses . These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Vitamin D is important for bone health and immune regulation , and has been shown to be low in multiple sclerosis ( MS ) . We sought to determine the effect of over the counter low dose cholecalciferol ( LDC ) and high dose ergocalciferol ( HDE ) on the vitamin D levels in MS patients . Methods We retrospectively evaluated serum 25-hydroxy-vitamin D [ 25(OH)D ] levels of 199 patients ( CIS , n = 32 ; RRMS , n = 115 ; PPMS , n = 10 ; SPMS , n = 16 ; Transverse Myelitis ( TM ) , n = 9 ; other neurological diseases , n = 16 ) attending our clinic between 2004 and 2008 . We examined the change in  25(OH)D levels in 40 MS patients who took either LDC ( ≤800 IU/day ) or HDE ( 50,000 IU/day for 7 - 10 days , followed by 50,000 IU weekly or biweekly ) . Results The average 25(OH)D level was 71 ± 39 nmol/L ( Mean ± SD ) , and 167(84 % ) patients had insufficient levels ( ≤100 nmol/L ) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels . However , 25(OH)D levels increased by 42 nmol/L ( P = 0.01 ) in the patients originally taking LDC and then prescribed HDE . Optimal levels ( ≥100 nmol/L ) were only achieved in less than 40 % of patients . Conclusions We conclude 
    Output:
    
agent
RESULTS / DISCUSSION Both cross-sectional and longitudinal studies have fairly consistently demonstrated a strong positive correlation between  vitamin D deficiency and subsequent relapse and /or disability in patients with MS .
As well , there appears to be a negative correlation between vitamin D levels and inflammatory markers in MS patients , suggesting that vitamin D modifies serum cytokines to a more anti-inflammatory profile .
However , the criteria of temporality , dose-response , and experimental evidence are yet to be adequately met , although there is preliminary evidence from longitudinal studies and r and omized clinical trials ( RCTs ) of supplementation that vitamin D can attenuate the autoimmune response in patients , and potentially reduce relapse rates and burden of disease .
Ultimately , the current evidence does not permit inference of a causal relationship between vitamin D deficiency and disease activity in MS .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: A group of young patients having multiple sclerosis was treated with dietary supplements containing calcium , magnesium and vitamin D for a period of one to two years . The experimental design employed self-pairing : the response of each patient was compared with his/her own case history as control . The number of exacerbations observed during the program was less than one half the number expected from case histories . No side effects were apparent . The dietary regimen may offer a new means of controlling the exacerbation rate in MS , at least for younger patients . The results tend to support a theory of MS which states that calcium and magnesium are important in the development , structure and stability of myelin Background A poor vitamin D status has been associated with a high disease activity of multiple sclerosis ( MS ) . Recently , we described associations between vitamin D status and peripheral T cell characteristics in relapsing remitting MS ( RRMS ) patients . In the present study , we studied the effects of high dose vitamin D3 supplementation on safety and T cell related outcome measures . Methodology /Principal Findings Fifteen RRMS patients were supplemented with 20 000 IU/d vitamin D3 for 12 weeks . Vitamin D and calcium metabolism were carefully monitored , and T cell characteristics were studied by flowcytometry . All patients finished the protocol without side-effects , hypercalcaemia , or hypercalciuria . The median vitamin D status increased from 50 nmol/L ( 31–175 ) at week 0 to 380 nmol/L ( 151–535 ) at week 12 ( P<0.001 ) . During the study , 1 patient experienced an exacerbation of MS and was censored from the T cell analysis . The proportions of ( naïve and memory ) CD4 + Tregs remained unaffected . Although Treg suppressive function improved in several subjects , this effect was not significant in the total cohort ( P = 0.143 ) . An increased proportion of IL-10 + CD4 + T cells was found after supplementation ( P = 0.021 ) . Additionally , a decrease of the ratio between IFN-γ+ and IL-4 + CD4 + T cells was observed ( P = 0.035 ) . Conclusion / Significance Twelve week supplementation of high  dose vitamin D3 in RRMS patients was well tolerated and did not induce decompensation of calcium metabolism . The skewing towards an anti-inflammatory cytokine profile supports the evidence on vitamin D as an immune-modulator , and may be used as outcome measure for upcoming r and omized placebo-controlled trials . Trial Registration Clinical trials.gov Objective : To determine whether interferon-β ( IFN-β ) medication use is associated with vitamin D levels and whether the two interact in exerting effects on relapse risk . Methods : In a prospect i ve cohort of 178 persons with clinical ly definite multiple sclerosis ( MS ) living in southern Tasmania in 2002–2005 ,  serum 25-hydroxyvitamin D [ 25(OH)D ] was measured biannually , with assessment by question naire for relevant factors , including IFN-β treatment . Results : Subjects reporting IFN-β use had significantly higher mean 25(OH)D than persons who did not ( p < 0.001 ) . This was mediated by an interaction between personal sun exposure and IFN-β , with treated persons realizing nearly three times 25(OH)D per hour of sun exposure of persons not on therapy . The association between 25(OH)D and 1,25-dihydroxyvitamin D did not differ by IFN-β therapy ( p = 0.82 ) . 25(OH)D was associated with a reduced relapse risk only among persons on IFN-β ( p < 0.001 ) . Importantly , IFN-β was only protective against relapse among persons with higher 25(OH)D ( hazard ratio [ HR ] 0.58 [ 95 % confidence interval ( CI ) 0.35–0.98 ] ) , while among 25(OH)D-insufficient persons , IFN-β  increased relapse risk ( HR 2.01 [ 95 % CI 1.22–3.32 ] ) . Conclusion : In this study , we found that IFN-β therapy is associated with greater production of vitamin D from sun exposure , suggesting part of the therapeutic effects of IFN-β on relapse in MS may be through modulation of vitamin D metabolism . These findings suggest persons being treated with IFN-β should have vitamin D status monitored and maintained in the sufficiency range . Classification of evidence : This study provided Class III evidence that IFN-β is associated with reduced risk of relapse , and this effect may be modified by a positive effect of IFN-β on serum 25(OH)D levels Background Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system in young adults . Despite the fact that numerous lines of evidence link both the risk of disease development and the disease course to the serum level of 25-hydroxyvitamin D it still remains elusive whether multiple sclerosis patients benefit from boosting the serum level of 25-hydroxyvitamin D , mainly because interventional clinical trials that directly address the therapeutic effects of vitamin D in multiple sclerosis are sparse . We here present the protocol of an interventional clinical phase II study to test the hypothesis , that high-dose vitamin D supplementation of multiple sclerosis patients is safe and superior to low-dose supplementation with respect to beneficial therapeutic effects . Methods / Design The EVIDIMS trial is a German multi-center , stratified , r and omized , controlled and double-blind clinical phase II pilot study . Eighty patients with the diagnosis of definite multiple sclerosis or clinical ly isolated syndrome who are on a stable immunomodulatory treatment with interferon-β1b will be r and omized to additionally receive either high-dose ( average daily dose 10.200 IU ) or low-dose ( average daily dose 200 IU ) cholecalciferol for a total period of 18 months . The primary outcome measure is the number of new lesions detected on T2-weighted cranial MRI at 3 tesla . Secondary endpoints include additional magnetic resonance imaging and optical coherence tomography parameters for neuroinflammation and -degeneration , clinical parameters for disease activity , as well as cognition , fatigue , depression , and quality of life . Safety and tolerability of high-dose vitamin D supplementation are further outcome parameters . Discussion In light of the discrepancy between existing epidemiological and pre clinical data on the one h and and available clinical data on the other the EVIDIMS trial will substantially contribute to the evaluation of the efficacy of high-dose vitamin D supplementation in MS patients . The study design presented here fulfills the criteria of a high- quality clinical phase II trial in MS.Trial Registration Clinical Trials.gov Identifier : CONTEXT Epidemiological and experimental evidence suggests that high levels of vitamin D , a potent immunomodulator , may decrease the risk of  multiple sclerosis .  There are no prospect i ve studies addressing this hypothesis . OBJECTIVE To examine whether levels of 25-hydroxyvitamin D  are associated with risk of multiple sclerosis . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study among more than 7 million US military personnel who have serum sample s stored in the Department of Defense Serum Repository . Multiple sclerosis cases were identified through Army and Navy physical disability data bases for 1992 through 2004 , and diagnoses were confirmed by medical record review . Each case ( n = 257 ) was matched to 2 controls by age , sex , race/ethnicity , and date s of blood collection . Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum sample s collected before the date of initial multiple sclerosis symptoms . MAIN OUTCOME MEASURES Odds ratios of multiple sclerosis associated with continuous or categorical levels ( quantiles or a priori-defined categories ) of serum 25-hydroxyvitamin D within each racial/ethnic group . RESULTS Among whites ( 148 cases , 296 controls ) , the risk of multiple sclerosis significantly decreased with increasing levels of 25-hydroxyvitamin D ( odds ratio [ OR ] for a 50-nmol/L increase in 25-hydroxyvitamin D , 0.59 ; 95 % confidence interval , 0.36 - 0.97 ) . In categorical analyses using the lowest quintile ( < 63.3 nmol/L ) as the reference , the ORs for each subsequent quintile were 0.57 , 0.57 , 0.74 , and 0.38 ( P = .02 for trend across quintiles ) . Only the OR for the highest quintile , corresponding to 25-hydroxyvitamin D levels higher than 99.1 nmol/L , was significantly different from 1.00 ( OR , 0.38 ; 95 % confidence interval , 0.19 - 0.75 ; P = .006 ) . The inverse relation with multiple sclerosis risk was particularly strong for 25-hydroxyvitamin D levels measured before age 20 years . Among blacks and Hispanics ( 109 cases , 218 controls ) , who had lower 25-hydroxyvitamin D levels than whites , no significant associations between vitamin D and multiple sclerosis risk were found . CONCLUSION The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis OBJECTIVE To determine whether low levels of 25-hydroxyvitamin D ( 25[OH]D ) contribute to the increased risk of postpartum multiple sclerosis ( MS ) relapses . DESIGN Prospect i ve cohort study . SETTING Out patients identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics . PATIENTS Twenty-eight pregnant women with MS . INTERVENTIONS We prospect ively followed up patients through the postpartum year and assessed exposures and symptoms through structured interviews .  Total serum 25(OH)D levels were measured using the DiaSorin Liaison Assay during the third trimester and 2 , 4 , and 6 months after giving birth . The data were analyzed using longitudinal multivariable methods . MAIN OUTCOME MEASURES Levels of 25(OH)D and relapse rate . RESULTS Fourteen ( 50 % ) women breastfed exclusively , and 12 women ( 43 % ) relapsed within 6 months after giving birth . During pregnancy , the average 25(OH)D levels were 25.4 ng/mL ( range , 13.7 - 42.6 ) and were affected only by season ( P=.009 ) . In contrast , in the postpartum period , 25(OH)D levels were significantly affected by breastfeeding and relapse status . Levels of 25(OH)D remained low in the exclusive breastfeeding group , yet rose significantly in the nonexclusive breastfeeding group regardless of season ( P=.007 , unadjusted ; P=.02 , adjusted for season ) . By 4 and 6 months after childbirth , 25(OH)D levels were , on average , 5 ng/mL lower in the women who breastfed exclusively compared with the nonbreastfeeding group ( P=.001 ) . CONCLUSIONS Pregnancy and exclusive breastfeeding are strongly associated with low 25(OH)D levels  in women with MS . However , these lower vitamin D levels were not associated with an increased risk of postpartum MS relapses . These data suggest that low vitamin D in isolation is not an important risk factor for postpartum MS relapses Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Vitamin D is important for bone health and immune regulation , and has been shown to be low in multiple sclerosis ( MS ) . We sought to determine the effect of over the counter low dose cholecalciferol ( LDC ) and high dose ergocalciferol ( HDE ) on the vitamin D levels in MS patients . Methods We retrospectively evaluated serum 25-hydroxy-vitamin D [ 25(OH)D ] levels of 199 patients ( CIS , n = 32 ; RRMS , n = 115 ; PPMS , n = 10 ; SPMS , n = 16 ; Transverse Myelitis ( TM ) , n = 9 ; other neurological diseases , n = 16 ) attending our clinic between 2004 and 2008 . We examined the change in  25(OH)D levels in 40 MS patients who took either LDC ( ≤800 IU/day ) or HDE ( 50,000 IU/day for 7 - 10 days , followed by 50,000 IU weekly or biweekly ) . Results The average 25(OH)D level was 71 ± 39 nmol/L ( Mean ± SD ) , and 167(84 % ) patients had insufficient levels ( ≤100 nmol/L ) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels . However , 25(OH)D levels increased by 42 nmol/L ( P = 0.01 ) in the patients originally taking LDC and then prescribed HDE . Optimal levels ( ≥100 nmol/L ) were only achieved in less than 40 % of patients . Conclusions We conclude 
    Output:
    