Benign and Malignant Breast Disease in South Wales: A Study of Urinary Steroids

The levels of aetiocholanolone, androsterone, and 17-hydroxycorticosteroids were measured in women without known disease of the breast, in women with benign breast disease, and in women with primary and advanced breast cancer. Statistical analysis showed there was no difference in the excretion of urinary 17-hydroxycorticosteroids in the various groups of patients. Detailed analysis of the aetiocholanolone and androsterone levels, however, indicated that patients with advanced localized disease excreted significantly less of these 11-deoxy-17-oxosteroids than those in the other groups.     

Thyrotropin Values in Patients with Micropapillary Thyroid Cancer Versus Benign Nodular Disease

ObjectivesStudies published in the last few years suggest that increased thyroid-stimulating hormone (TSH) values are associated with increased risk of thyroid cancer and/or a more advanced stage of malignancy. The aim of this study was to explore the hypothesis that TSH may be a risk factor for thyroid cancer initiation, which was tested by comparing TSH concentrations in patients with incidental micro papillary cancer (mPTC) and controls with a negative histologic exam.MethodsPatients were retrospectively selected from medical records from 3 district hospitals. Patients with biochemical/histologic evidence of autoimmunity, thyroid function-interfering drugs, and autonomously functioning areas, were excluded. TSH values of 41 patients with an incidental mPTC were then compared with a sex-and age-matched group of patients who had a negative histologic exam at a 4:1 ratio (164 patients).ResultsTSH was not significantly different in the mPTC group compared to the controls (1.1 ± 0.7 vs. 1.3 ± 1.0 mIU/L). After adjustment for age and gender, TSH levels were still not found to be significantly different between groups. In the mPTC group, TSH levels were not found to be a significant predictor of tumor size after adjusting for age and gender (β = 0.035, SE = 0.73, P = .844).ConclusionsOn the basis of these results, the hypothesis that TSH is involved in de novo oncogenesis of PTC is not supported. (Endocr Pract. 2013;19:651-655)     

3,3'-Diiodothyronine Concentrations in Hospitalized or Thyroidectomized Patients: Results from a Pilot Study

ObjectiveTo determine if various medical conditions affect the serum concentrations of 3,3′-diiodothyronine (3,3′-T2).MethodsA total of 100 patients who were recruited from a group of inpatients and outpatients with a diverse range of medical conditions, donated a single blood sample that was assayed for thyroid hormone derivatives using liquid-chromatography tandem mass spectrometry (LC-MS/MS). The associations between 3,3′-T2 concentrations and physiologic data and medical conditions were assessed.ResultsHigher quartiles of 3,3′-T2 concentrations (quartile 1: 2.01-7.48, quartile 2: 7.74-12.4, quartile 3: 12.5-17, quartile 4: 17.9-45.8 pg/mL) were associated with decreasing occurrence of critical illness (58%, 11%, 0%, 8%), stroke (29%, 7.7%, 4%, 0%), critical care unit hospitalization (75%, 39%, 8.3 %, 12%), and inpatient status (83%, 42%, 8%, 12%) (all P < .001). The same quartiles were associated with increasing frequency of thyroidectomy (4%, 12%, 17%, 60%). In multivariate analyses, after adjustment for age and sex, inpatient status was associated with decreasing concentrations of 3,3′-T2 (46% decrease for inpatients with 95% confidence interval [CI] 32-57%, P < .0001). Thyroidectomy was associated with increasing concentrations of 3,3′-T2 (29% increase (CI 0.5-66%, P = .049).ConclusionWe observed associations between inpatient status and reduced 3,3′-T2 concentrations. This appears to be a global change associated with illness, rather than an association with specific medical conditions. We also observed higher 3,3′-T2 concentrations in athyreotic outpatients receiving thyroid-stimulating hormone (TSH) suppression therapy. This demonstrates that there is production of 3,3′-T2 from levothyroxine (LT4) in extrathyroidal tissues. Conversion of thyroxine (T4) to 3,3′-T2 via both triiodothyronine (T3) and reverse triiodothyronine (rT3) pathways may prevent excessive T3 concentrations in such patients. (Endocr Pract. 2014;20:797-807)     

Longitudinal Study of CSF Biomarkers in Patients with Alzheimer's Disease

Background

The CSF biomarkers tau and Aβ42 can identify patients with AD, even during the preclinical stages. However, previous studies on longitudinal changes of tau and Aβ42 in individual patients with AD and elderly controls report somewhat inconsistent results.

Methodology/Principal Findings

We investigated the levels of tau and Aβ42 at baseline and after 1 year in 100 patients with AD. In a second cohort of 45 AD patients we measured the CSF biomarkers at baseline and after 2 years. Moreover, in 34 healthy elderly controls the CSF biomarkers were followed for 4 years. The baseline levels of tau were increased with >60% in AD patients compared to controls (p<0.001), while baseline Aβ42 levels were decreased with >50% (p<0.001). In the AD group followed for 2 years, tau increased with 16% compared to the baseline levels (p<0.05). However, the levels of tau were stable over 4 years in the controls. The levels of Aβ42 did not change significantly over time in any of the groups. In the patients with AD, tau was moderately associated with worse cognitive performance already at baseline (p<0.05).

Conclusions/Significance

Tau and Aβ42 in CSF seem to reflect the underlying disease state in both early and late stages of AD. The slight increase in tau over time observed in the patients with AD is modest when compared to the relatively large difference in absolute tau levels between AD patients and controls. Therefore, these markers maintain their usefulness as state markers over time and might serve as surrogate markers for treatment efficacy in clinical trials.     

Comparison of Trace Elements in the Scalp Hair of Malignant and Benign Breast Lesions Versus Healthy Women

Trace elements including Al, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, Sb, Sr, and Zn were analyzed in the scalp hair samples of women with malignant breast lesions, women with benign breast lesions, and healthy donors using atomic absorption spectrophotometric method. In the scalp hair of malignant-tumor patients, the highest average concentration was shown by Ca (1,187 μg/g), followed by Na (655 μg/g), Mg (478 μg/g), Zn (391 μg/g), Sr (152 μg/g), Fe (114 μg/g), and K (89.8), while in the case of benign-tumor patients, the average estimated element levels were 1,522, 1,093, 572, 457, 217, 80.4, and 74.7 μg/g, respectively. Most of the elements exhibited non-normal distribution evidenced by large spread, standard error, and skewness values. Mean concentrations of Ca (634 μg/g), Zn (206 μg/g), Mg (162 μg/g), Fe (129 μg/g), and Na (82.1 μg/g) were noteworthy in the scalp hair of healthy women. Average levels of Na, Sr, K, Cd, Co, Pb, Mg, Ca, Zn, Ni, Sb, and Mn were revealed to be significantly higher in the hair of malignant and benign patients compared to the healthy women; however, Fe, Cu, Al, and Cr were not significantly different in the scalp hair of the three groups. The quartile distributions of Ca, Cd, Co, Cr, K, Mg, Mn, Na, Ni, Pb, Sb, and Sr revealed maximum spread in the scalp hair of malignant and benign groups; nevertheless, Al, Cu, Fe, and Zn exhibited almost comparable quartile levels in the three groups. Strong correlation coefficients were found between Fe and Cd, Al and Na, Mn and Sr, Co and Cr, Cd and Cr, Pb and K, Pb and Mn, Cu and Na, and Al and Fe in the scalp hair of malignant-tumor patients, while Fe and K, Cd and Co, Na and Co, and Cr and Pb showed strong correlations in the scalp hair of benign-tumor patients, both of which were significantly different compared with the healthy subjects. Multivariate cluster analysis also revealed divergent clustering of the elements in the scalp hair of malignant and benign patients in comparison with the healthy women.     

Neural Substrates of Cognitive Subtypes in Parkinson's Disease: A 3-Year Longitudinal Study

Background

The neuropsychological features and neuropathological progression patterns associated with rapidly evolving cognitive decline or dementia in Parkinson''s disease (PD) remain to be elucidated.

Methods

Fifty-three PD patients without dementia were recruited to participate in a 3-year longitudinal cohort study. The patients were grouped according to the Clinical Dementia Rating (CDR). Group-wise comparisons were made with regard to demographic characteristics, motor symptoms, neuropsychological performances and 18F-fluorodeoxyglucose positron emission tomography.

Results

Patients who had memory-plus cognitive impairment (patients whose CDR was 0 at baseline and 0.5 in memory and other domains at follow-up, and those whose baseline CDR was 0.5 in memory and other domains) exhibited higher age at onset, visuoperceptual impairment, non-tremor-dominant motor disturbance, rapid symptomatic progression and posterior neocortical hypometabolism. In patients who were cognitively unimpaired and those who had memory-dominant cognitive impairment (patients whose CDR was 0 at baseline and 0.5 only in memory domain at follow-up, and those whose baseline CDR was 0.5 only in memory domain), the posterior neocortex was relatively unaffected until a later stage of the disease.

Conclusions

These results suggest that visuoperceptual impairment and the early involvement of the posterior neocortex may be risk factors for rapid symptomatic progression and dementia in PD.     

Inflammation,Endothelial Dysfunction and Increased Left Ventricular Mass in Chronic Kidney Disease (CKD) Patients: A Longitudinal Study

Introduction

Within this longitudinal study we investigated the association of inflammation markers C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) and endothelial dysfunction markers intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) with left ventricular mass indexed for height²·⁷¹ (LVMI) in hypertensive predialysis CKD patients.

Material and Methods

From 2004 to 2005, 182 incident consecutive adult patients from the outpatient CKD clinics of two hospitals in Greece with CKD and hypertension or using antihypertensive medication, were included. Of these, 107 patients underwent CRP (mg/l) and LVMI (g/height²·⁷¹) measurements annually for three years.

Results

In the longitudinal analyses, using linear mixed modeling, a higher IL-6 (ß = 1.9 (95%ci:0.38;3.5), inflammation score based on CRP, IL-6 and TNF-α (ß = 5.0 (95%ci:0.72; 9.4) and VCAM-1 (ß = 0.01 (95%ci:0.005;0.02) were associated with higher LVMI. These models were adjusted for age, gender and primary renal disease, and for confounders that on top changed the beta with ≥10%, i.e. diuretic use (for IL-6 and inflammation score).

Conclusion

The results suggest that in predialysis CKD patients, inflammation as well as endothelial dysfunction may play an important role towards the increase in LVMI.     

Drug-Related Problems in Patients with Benign Prostatic Hyperplasia: A Cross Sectional Retrospective Study

Benign Prostatic Hyperplasia (BPH) patients are at risk of acquiring drug-related problems (DRPs), as it is present in the majority of aging men. To date, DRPs among BPH patients have not been well studied. We conducted this retrospective study in a tertiary hospital in Malaysia from January 2009 to June 2012 with the aim of identifying the factors associated with DRPs among BPH patients. The Pharmaceutical Care Network Europe Classification Version (PCNE) 5.01 was used as a tool to classify DRPs. We enrolled 203 patients from 259 hospital admissions. A total of 390 DRPs were found and there was an average of 1.5±1.3 problems per hospitalization. 76.1% of hospital admissions included at least one DRP. The most common DRP categories encountered were drug choice problems (45.9%), drug interactions (24.9%), and dosing problems (13.3%). Factors such as advanced age (p = 0.005), a hospital stay of more than 6 days (p = 0.001), polydrug treatments (p<0.001), multiple comorbidities (p<0.001), and comorbid cardiovascular disease (p = 0.011), diabetes mellitus(p = 0.001), hypertension (p<0.001) and renal impairment (p = 0.011) were significantly associated with the occurrence of DRPs. These data indicated that the prevalence of DRPs is high among BPH patients. The identification of different subtypes of DRPs and the factors associated with DRPs may facilitate risk reduction for BPH patients.     

The Incidence of Inflammatory Bowel Disease in Northern China: A Prospective Population-Based Study

Aims & Backgrounds

Although inflammatory bowel diseases (IBD) are emerging and increasing in China, epidemiologic data are rarely available. This study was to investigate the epidemiological and clinical characteristics of IBD in Northern China.

Methods

This is a prospective, population-based study of incidence of IBD in Daqing,Heilongjiang province of Northern China from March 1, 2012 to February 28, 2013. All incident patients with IBD were clinically identified by IBD specialist group from five main General Hospitals covering the healthcare service for 1,343,364 residents in the urban areas of Daqing. IBD cases included in this study were followed-up for three months for diagnosis confirmation.

Results

A total of 27 new IBD cases including 25 cases of ulcerative colitis (UC) and 2 cases of Crohn''s disease (CD) were identified. The population at risk was 1,343,364 person years. Age-adjusted incidence for total IBD, CD and UC were 1.77, 0.13, and 1.64 per 100,000population, respectively. A male predominance was found in CD patients (male to female ratio was 2∶0). In contrast, no obvious gender predominance was found in UC patients (male to female ratio was 1∶1.1). CD patients were diagnosed at an average age of 39.5 years. The main disease phenotypes of UC were distal colitis with a 24% of proctitis and 56% of left-sided colitis. The mean diagnostic age of UC patients was 48.9 years.

Conclusions

This is the first report on the incidence of IBD in the Northern Chinese population. A lower incidence of IBD, similar male predominance for CD, similar disease phenotype of UC, and lower disease activity was observed in Daqing compared to that in Southern China.     

Predicting Risk of Motor Vehicle Collisions in Patients with Glaucoma: A Longitudinal Study

Purpose

To evaluate the ability of longitudinal Useful Field of View (UFOV) and simulated driving measurements to predict future occurrence of motor vehicle collision (MVC) in drivers with glaucoma.

Design

Prospective observational cohort study.

Participants

117 drivers with glaucoma followed for an average of 2.1 ± 0.5 years.

Methods

All subjects had standard automated perimetry (SAP), UFOV, driving simulator, and cognitive assessment obtained at baseline and every 6 months during follow-up. The driving simulator evaluated reaction times to high and low contrast peripheral divided attention stimuli presented while negotiating a winding country road, with central driving task performance assessed as “curve coherence”. Drivers with MVC during follow-up were identified from Department of Motor Vehicle records.

Main Outcome Measures

Survival models were used to evaluate the ability of driving simulator and UFOV to predict MVC over time, adjusting for potential confounding factors.

Results

Mean age at baseline was 64.5 ± 12.6 years. 11 of 117 (9.4%) drivers had a MVC during follow-up. In the multivariable models, low contrast reaction time was significantly predictive of MVC, with a hazard ratio (HR) of 2.19 per 1 SD slower reaction time (95% CI, 1.30 to 3.69; P = 0.003). UFOV divided attention was also significantly predictive of MVC with a HR of 1.98 per 1 SD worse (95% CI, 1.10 to 3.57; P = 0.022). Global SAP visual field indices in the better or worse eye were not predictive of MVC. The longitudinal model including driving simulator performance was a better predictor of MVC compared to UFOV (R² = 0.41 vs R² = 0.18).

Conclusions

Longitudinal divided attention metrics on the UFOV test and during simulated driving were significantly predictive of risk of MVC in glaucoma patients. These findings may help improve the understanding of factors associated with driving impairment related to glaucoma.     

A Probable Risk Factor of Female Breast Cancer: Study on Benign and Malignant Breast Tissue Samples

The study reports enhanced Fe, Cu, and Zn contents in breast tissues, a probable risk factor of breast cancer in females. Forty-one formalin-fixed breast tissues were analyzed using atomic absorption spectrophotometry. Twenty malignant, six adjacent to malignant and 15 benign tissues samples were investigated. The malignant tissues samples were of grade 11 and type invasive ductal carcinoma. The quantitative comparison between the elemental levels measured in the two types of specimen (benign and malignant) tissues (removed after surgery) suggests significant elevation of these metals (Fe, Cu, and Zn) in the malignant tissue. The specimens were collected just after mastectomy of women aged 19 to 59 years from the hospitals of Islamabad and Rawalpindi, Pakistan. Most of the patients belong to urban areas of Pakistan. Findings of study depict that these elements have a promising role in the initiation and development of carcinoma as consistent pattern of elevation for Fe, Cu, and Zn was observed. The results showed the excessive accumulation of Fe (229?±?121 mg/L) in malignant breast tissue samples of patients (p?<?0.05) to that in benign tissues samples (49.1?±?11.4 mg/L). Findings indicated that excess accumulation of iron in malignant tissues can be a risk factor of breast cancer. In order to validate our method of analysis, certified reference material muscle tissue lyophilized (IAEA) MA-M-2/TM was analyzed for metal studied. Determined concentrations were quite in good agreement with certified levels. Asymmetric concentration distribution for Fe, Cu, and Zn was observed in both malignant and benign tissue samples.     

Prevention of Postoperative Deep Vein Thrombosis in Patients with Malignant Disease

We have used the ¹²⁵I-fibrinogen test to asses the value of an improved method of peroperative intermittent calf compression as a prophylactic measure against postoperative thrombosis. In a group of 99 patients over the age of 40 undergoing operations lasting more than 30 minutes the technique reduced the incidence of postoperative thrombosis by over 75%. In patients suffering from malignant disease, who are generally considered to be in the very high risk category, the reduction achieved was almost 90%.     

Postoperative Depression of Tumour-directed Cell-mediated Immunity in Patients with Malignant Disease

Leucocytes from 46 melanoma patients, 45 breast carcinoma patients, and 95 control donors were tested by the leucocyte migration test against the supernatants of homogenates of malignant melanomas, breast carcinomas, simple breast tumours, and breasts showing simple cystic disease. By comparison with controls inhibition of migration occurred significantly more frequently when tumour patients'' leucocytes were exposed to extracts of histogenetically similar tumours.Cell-mediated immunity to tumour-associated antigens was measured in 12 patients with breast carcinoma and 12 with malignant melanoma immediately before surgical operation and in the postoperative period. All patients tested before operation showed significant inhibition of migration on contact with extracts of histogenetically similar tumours. Postoperatively the degree of leucocyte migration inhibition was reduced in all patients with melanoma and breast carcinoma. Significant inhibition of leucocyte migration returned in most patients 6-22 days after operation.     

Childhood Hospitalisation with Infection and Cardiovascular Disease in Early-Mid Adulthood: A Longitudinal Population-Based Study

BackgroundPathogen-specific and overall infection burden may contribute to atherosclerosis and cardiovascular disease (CVD), but the effect of infection severity and timing is unknown. We investigated whether childhood infection-related hospitalisation (IRH, a marker of severity) was associated with subsequent adult CVD hospitalisation.MethodsUsing longitudinal population-based statutorily-collected administrative health data from Western Australia (1970-2009), we identified adults hospitalised with CVD (ischaemic heart disease, ischaemic stroke, and peripheral vascular disease) and matched them (10:1) to population controls. We used Cox regression to assess relationships between number and type of childhood IRH and adulthood CVD hospitalisation, adjusting for sex, age, Indigenous status, socioeconomic status, and birth weight.Results631 subjects with CVD-related hospitalisation in adulthood (≥ 18 years) were matched with 6310 controls. One or more childhood (< 18 years) IRH was predictive of adult CVD-related hospitalisation (adjusted hazard ratio, 1.3; 95% CI 1.1-1.6; P < 0.001). The association showed a dose-response; ≥ 3 childhood IRH was associated with a 2.2 times increased risk of CVD-related hospitalisation in adulthood (adjusted hazard ratio, 2.2; 95% CI 1.7-2.9; P < 0.001). The association was observed across all clinical diagnostic groups of infection (upper respiratory tract infection, lower respiratory tract infection, infectious gastroenteritis, urinary tract infection, skin and soft tissue infection, and other viral infection), and individually with CVD diagnostic categories (ischaemic heart disease, ischaemic stroke and peripheral vascular disease).ConclusionsSevere childhood infection is associated with CVD hospitalisations in adulthood in a dose-dependent manner, independent of population-level risk factors.     

Platelet Lysate Mucohadesive Formulation to Treat Oral Mucositis in Graft Versus Host Disease Patients: A New Therapeutic Approach

Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2–8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.KEY WORDS: in vitro proliferation and wound healing test, in vivo assessment in graft versus host disease, mucositis, platelet lysate growth factors     

The Association between Nutritional Status and Malaria in Children from a Rural Community in the Amazonian Region: A Longitudinal Study

Background

The relationship between malaria and undernutrition is controversial and complex. Synergistic associations between malnutrition and malaria morbidity and mortality have been suggested, as well as undernutrition being protective against infection, while other studies found no association. We sought to evaluate the relationship between the number of malaria episodes and nutritional statuses in a cohort of children below 15 years of age living in a rural community in the Brazilian Amazon.

Methodology/Principal Findings

Following a baseline survey of clinical, malaria and nutritional assessment including anthropometry measurements and hemoglobin concentration, 202 children ranging from 1 month to 14 years of age were followed for one year through passive case detection for malaria episodes. After follow-up, all children were assessed again in order to detect changes in nutritional indicators associated with malaria infection. We also examined the risk of presenting malaria episodes during follow-up according to presence of stunting at baseline. Children who suffered malaria episodes during follow-up presented worse anthropometric parameters values during this period. The main change was a reduction of the linear growth velocity, associated with both the number of episodes and how close the last or only malaria episode and the second anthropometric assessment were. Changes were also observed for indices associated with chronic changes, such as weight-for-age and BMI-for-age, which conversely, were more frequently observed in children with the last or only episode occurring between 6 and 12 months preceding the second nutritional assessment survey. Children with inadequate height-for-age at baseline (Z-score < -2) presented lower risk of suffering malaria episodes during follow-up as assessed by both the log-rank test (p =0.057) and the multivariable Cox-proportional hazards regression (Hazard Ratio = 0.31, 95%CI [0.10; 0.99] p=0.049).

Conclusions

Malaria was associated with impaired nutritional status amongst children in an endemic area of the Western Brazilian Amazon where P. vivax predominates. Our data all supports that the association presents differential effects for each age group, suggesting distinct pathophysiology pathways. We were also able to demonstrate that undernourishment at baseline was protective to malaria during follow-up. These findings support an intriguing interaction between these conditions in the rural Amazon and the need for a more integrative approach by health systems in endemic areas.     

Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study

Objectives

To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.

Methods

The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.

Results

Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm³) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.

Conclusions

Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.