Total urinary polyphenols and longitudinal changes of bone properties. The InCHIANTI study.

The aim of this study was to evaluate the association of levels of urinary total polyphenols considered as a proxy measure of polyphenol intake, with longitudinal changes of bone properties, in the InCHIANTI study. Dietary intake of polyphenols appears to be associated with future accelerated deterioration of bone health. INTRODUCTION: Polyphenols, micronutrients ingested through plant-based foods, have antioxidant and anti-inflammatory properties and may contribute to osteoporosis prevention. We evaluated associations of high levels of urinary total polyphenols (UTP), a proxy measure of polyphenol intake, with longitudinal changes of bone properties in a representative cohort of free-living participants of the InCHIANTI study. METHODS: The InCHIANTI study enrolled representative samples from the registry list of two towns in Tuscany, Italy. Baseline data were collected in 1998 and follow-up visits in 2001 and 2004. Of the 1453 participants enrolled, 956 consented to donate a 24-h urine sample used to assess UTP, had dietary assessment, a physical examination, and underwent a quantitative computerized tomography (pQCT) of the tibia. From pQCT images, we estimated markers of bone mass (BM), diaphyseal design (DD), and material quality (MQ). Mixed models were used to study the relationship between baseline tertiles of UTP with changes of the bone characteristics over the follow-up. RESULTS: At baseline, higher levels of UTP were positively correlated with markers of BM, DD, and MQ. Compared with lower tertile of UTP, participants in the intermediate and highest tertiles had higher cortical bone area, cortical mineral content, and cortical thickness. However, participants in the intermediate and highest UTP tertiles experienced accelerated deterioration of these same parameters over the follow-up compared with those in the lowest UTP tertile. CONCLUSIONS: Dietary intake of polyphenols estimated by UTP and dietary questionnaire was associated with long-term accelerated deterioration of bone health. Our study does not support the recommendation of increasing polyphenol intake for osteoporosis prevention.

Exploratory study on immune phenotypes in Alzheimer's disease and vascular dementia.

BACKGROUND AND PURPOSE: The differentiation of Alzheimer's disease (AD) dementia from vascular dementia (VaD) and mixed-type dementia (mixed dementia) requires stepwise analysis and usually occurs late in the disease process. Early diagnosis and therapy monitoring would benefit greatly from the identification of biomarkers of neurodegeneration, especially blood biomarkers. To this end, the aim of the present pilot study was to investigate differences in the distribution of peripheral T-cell populations in patients with AD compared to VaD and mixed dementia. METHODS: Flow cytometry was performed on blood samples from 11 patients with AD, six with VaD and six with mixed dementia, as well as 17 healthy control subjects (HCs). CD4+ and CD8+ T cells were typed for expression of CD45, CD27, CD28, CD25, FoxP3, CCR4 and CCR6; the other leukocytes were also assessed. Functionally, immune cell uptake of the ß-amyloid (Aß) toxic fragment (Aß1-42 ) was also evaluated. RESULTS: A higher proportion of CD4+CD28- memory T cells and a reciprocal reduction of CD4+CD28+CD27+ naïve T lymphocytes was detected in all patient groups relative to controls. Significantly fewer CD4+CD25+FoxP3 regulatory T cells were present in patients with VaD, and significantly more CCR6+ and CCR4+ CD4+ T cells in those with AD. Higher CCR6+ T-cell frequencies were also present in patients with mixed dementia, potentially due to the inflammation and immune cell chemoattraction triggered by Aß. CONCLUSIONS: The present study was a comprehensive investigation comparing different kinds of dementia, revealing differentially expressed peripheral markers that are potentially useful for early AD, VaD and mixed dementia diagnoses, and that would assist in proper treatments for these disparate diseases. Validation is now required.

Oral health of elite athletes and association with performance: a systematic review.

BACKGROUND: We aimed to systematically review the epidemiology of oral disease and trauma in the elite athlete population and to investigate the impact of oral health on sporting performance. METHODS: Authors searched Ovid MEDLINE (1950 to October 2013), Ovid EMBASE (1980 to October 2013), EBSCO SPORTDiscus (up to October 2013) and OpenGrey (http://www.opengrey.eu). No date or language restrictions were applied. Papers were included if they evaluated the oral health of professional athletes. The methodological quality of papers was evaluated using a modification of the Newcastle-Ottawa scale. RESULTS: The literature search led to 9858 potentially relevant citations. Following a set of predefined exclusion criteria, 34 studies remained. Twenty-six studies reported on dental trauma, which ranged in prevalence from 14% to 47% varying by sport and country. Sixteen studies considered the oral health of athletes and reported high prevalence of oral diseases: dental caries 15-75%, dental erosion 36-85%, periodontal disease 15%. In four studies, a range between 5% and 18% of athletes reported negative impact of oral health or trauma on performance. The methodological quality of included studies was generally low. CONCLUSIONS: Within the limits of the review, oral health of athletes is poor. We hypothesise that poor oral health associates with self-reported performance; however, this needs to be tested. Further studies on representative samples of athletes are needed to assess the size of the problem of poor oral health as well as to investigate the possible impact on performance using objective measures of performance.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

Microalbuminuria and hypertension in HIV-infected patients: a preliminary study of telmisartan.

BACKGROUND: There is increasing evidence of hypertension and microalbuminuria in HIV-infected patients, and these are two important risk factors for renal and cardiovascular disease. Anti-hypertensive drugs inhibiting the renin-angiotensin system exert an antiproteinuric effect. Telmisartan, an angiotensin II receptor blocker and partial peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist that is approved for the treatment of hypertension, appears to exert a nephroprotective effect independent of blood pressure reduction in the general population. OBJECTIVE: The aim of this preliminary study was to evaluate possible nephroprotective effects of telmisartan in hypertensive HIV-positive patients with microalbuminuria. PATIENTS AND METHODS: Caucasian male patients with HIV infection (n=13) receiving stable combined antiretroviral therapy (without therapeutic changes for > 12 months) and a recent diagnosis of grade 1 hypertension were treated with daily oral telmisartan 80 mg for 6 months. Patients had suppressed viremia and a CD4 cell count > 300 cells/mL for 6 months, and microalbuminuria > 5 mg/dL. Systolic and diastolic blood pressure (SBP, DBP), triglycerides, total cholesterol, HDL cholesterol and LDL cholesterol, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), microalbuminuria, Modification of Diet Renal Disease-Glomerular Filtration Rate (MDRD-GFR), vascular endothelial growth factor (VEGF) and endothelin-1 were measured at baseline and at one, three and six months. All statistical analyses were performed using SAS 9.2. RESULTS: A significant reduction of microalbuminuria (p < 0.001) with stable MDRD-GFR was observed, although the main indices of renal function showed no substantial change. A significant reduction in mean SBP and DBP was observed at T1 and confirmed at T3 and T6 (SBP p < 0.001 and DBP p < 0.001), and there was BP normalization. Metabolic assessments showed an improvement in lipid parameters, and a significant decrease in insulin resistance assessed by the homeostasis model assessment index-insulin resistance (HOMA-IR) (p = 0.04). In addition, there was a statistically significant reduction in ESR (p = 0.02) and a non significant reduction in CRP. Other results included a significant reduction in serum VEGF and endothelin-1 levels (p < 0.001). CONCLUSIONS: From these preliminary findings, telmisartan has demonstrated efficacy in the control of hypertension and microalbuminuria in HIV-infected patients. Decreased microalbuminuria with stable MDRD-GFR may be indicative of a nephroprotective effect of telmisartan; mechanisms causing microalbuminuria in patients with HIV could be related to infection, chronic inflammation, and endothelial dysfunction. The decreased endothelin-1 and VEGF levels in patients in this study may be related to an endothelial protective effect of telmisartan. This study reports the first observation of renal and endothelial protective effects of telmisartan in HIV-positive patients.

Molecular approach by PCR is the best method to detect the presence of Chlamydia trachomatis and to define the true agent of ocular bacterial inflammation.

Chlamydia trachomatis (Ct) is an atypical agent for acute, subclinical and chronic conjunctivitis in developed countries, as stated by the International League against Trachoma. In order to evaluate the presence of Ct, from a total of 3,520 patients visiting the consulting room of the Eye Clinic of the University of Chieti, Italy from 2006-2008, we enrolled 171 patients affected by occasional mild, moderate or severe conjunctivitis in a three-arm prospective open study, using traditional analysis such as Immune Fluorescent Assay and Enzyme–Linked Fluorescent Assay (IFA and ELFA) and molecular analysis with Polymerase Chain Reaction (PCR) procedure for Ct DNA research (Ct DNA). At the same time, microbiological culture was carried out for common germs and mycetes. These patients were analyzed at different subsequent times. In the first arm (Group A) of 82 patients with IFA and ELFA only 10 people (12.2%) resulted positive to Ct infection with both methods. The presence of Ct was never alone, but always overlapped with contaminants, like corynebacteria, staphylococci, streptococci and colonbacteria, randomly distributed, while no growth of mycetes was observed. Of these positive patients, only one 47-year-old female, suffering from a moderate form of ocular chlamydial infection, showed serological conversion against this infection; furthermore, this female had also been suffering from reactive arthritis for sometime. In the second arm (Group B) of 89 patients, we carried out PCR for Ct detection: 82 (94.25%) were found positive to Ct – DNA research, with common germ growth randomly associated, without sex or age prevalence, as in group A; no mycetes were found. The third arm (Group C) included 37 negative patients from Group A with severe or moderate chronic conjunctivitis, randomly recruited between relapsing cases, with the addition of the single previously positive seroconversion case, for a total of 38 patients, who were re-evaluated by PCR Ct-DNA analysis. All these patients, negative to IFA and ELFA, were positive to Ct-DNA analysis. These data indicate a higher rate of Ct infection in patients with severe or moderate chronic conjunctivitis, resistant to usual therapies even after eradication of common germs, thus showing the advantage of introducing this molecular technique of analysis in mild to severe chronic or recurrent conjunctivitis.

Protracted benefit from paradoxical kinesia in typical and atypical parkinsonisms.

Paradoxical kinesia (PK) is the sudden resolution of a previously stabilized akinesia in an advanced idiopathic Parkinson's disease (IPD) patient facing an immediate threat. We are reporting the effect of PK, as a consequence of a life threatening event (earthquake), in a group of 14 patients with parkinsonism and dementia in Hoehn/Yahr (H/Y) stage 3-5. All the patients presented an extraordinary motor response during the earthquake that has recently stricken the Italian city of L'Aquila. All of them were able to safely escape unaided and, in some cases, to assist their families, despite they suffered before from severe night time akinesia and gait difficulties with postural instability requiring assistance. In five patients, the improvement of motor disabilities, particularly of freezing, lasted for 2-5 months.

Ultrasound-guided hyaluronic acid injection in carpometacarpal osteoarthritis: short-term results.

Carpometacarpal osteoarthritis (CMC-OA) is a disabling condition, characterized by pain and functional impairment. The aim of the present study is to evaluate the efficacy of a single ultrasoundguided injection of hyaluronic acid (HA) in patients suffering from CMC-OA. Eighteen patients with CMC-OA, grade 2-3 Kellgren and Lawrence score, attending the Orthopaedic Department of the University Hospital of Chieti, were enrolled. They underwent clinical evaluation at baseline and after one month follow-up, evaluating: grading of pain (VAS at rest and during activities), function (Dreiser Index), grip and pinch strengths Jamar dynamometer), as well as NSAIDs consumption. Each patient received a single ultrasound- guided injection of HA into the articular CMC joint. The results were that pain at rest and during activities decreased from 1.8 +/= 1.07 to 0.5 +/= 0.68 (p < 0.001) and from 8.05 +/= 0.94 to 4.15 +/= 1.42 (p < 0.001), respectively. Dreiser Functional Index showed a significant improvement (+11.59 percent; p < 0.004), as well as pulp pinch strength (24.07 percent; p < 0.001). The consumption of NSAIDs was also clearly reduced, from 16 to 7 patients (-45 percent) and from 2.45 +/= 1.98 to 1.15 +/= 1.30 tablets per week (p < 0.02). Mild local side effects, lasting less than 3 hours, were observed only in 2 cases. A single ultrasound guided injection of HA is a safe and effective procedure in CMC-OA, with a significant improvement in terms of pain and function. However, studies with larger samples and longer term follow-up are warranted.

Dietary antioxidants as potential pharmacological agents for ischemic stroke.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Frailty in the elderly: the physical dimension.

Frailty may be considered as a vulnerable status, which can precede the onset of overt disability. Operational definitions of frailty vary widely according to the conceptual framework: some authors consider frailty in a broad sense, which encompasses the physical, social, cognitive, psychological dimensions and comorbidity, whereas others define the syndrome more restrictively, mainly on the basis of performance parameters, such as gait speed, grip strength and physical activity. All these definitions are provided of a high predictive value for adverse outcomes, such as disability, hospitalization and mortality. Sarcopenia (i.e. the reduction of muscular mass and function) plays a predominant role in the pathogenesis of frailty. Among the factors responsible for sarcopenia (such as proinflammatory cytokines, low growth hormone and testosterone levels, increased production of oxygen free radicals, malnutrition and reduced neurological drive), immobility and lack of exercise have a preponderant role. Therefore, the diagnosis of frailty is mandatory for the early identification of a subset of elderly subjects at high risk, which can receive benefit from rehabilitation. A self-report and objective evaluation of physical performance are the best indicators of frailty in elderly subjects, a poor performance suggesting the need of an early and proper intervention. Structured exercise programs are effective in contrasting the progression of frailty, but an healthy and active lifestyle may be sufficient for delaying the onset of disability. In conclusion, there is clear evidence for prescription of exercise within the mainstream of the medical practice, rather than as an optional adjunct to standard care of the oldest old, given the public health implication of frailty, whose prevalence is going to increase in western populations.

Frailty of older age: the role of the endocrine--immune interaction.

The so-called demographic transition has changed the age structure of the population worldwide, with profound effects on societal organization. The growing number and percentage of old and very old people has compelled the scientific community to focus on age related diseases and peculiar consequences of aging itself such as disability and frailty. Understanding the pathophysiology of frailty, a syndrome characterized by a reduced functional reserve and impaired adaptive capacity that results from cumulative declines of multiple subsystems, and causes increased vulnerability to adverse outcomes, is a major topic in aging research. Aging processes induce multiple changes in the hormones network (menopause, andropause, somatopause and adrenopause), in the immune system, and can modulate their efficiency and effectiveness in determining a response to stressors. These triggering events can unmask frailty in older people. Starting from these assumptions, we analyzed the relationship of the endocrine and immune networks in aging and in the different domains that are characteristically associated with the frailty syndrome, such as disability and sarcopenia, as well as in diseases related to aging such as Alzheimer's dementia and Congestive Heart Failure.

Correlates of bone quality in older persons.

PURPOSE OF THE STUDY: In a population-based sample of older persons, we studied the relationship between tibial bone density and geometry and factors potentially affecting osteoporosis. METHODS: Of the 1260 participants aged 65 years or older eligible for the InCHIANTI study, 1155 received an interview and 915 (79.2%) had complete data on tibial QCT scans and other variables used in the analysis presented here. The final study population included 807 persons (372 men and 435 women, age range 65-96 years) after exclusion of participants affected by bone diseases or treated with drugs that interfere with bone metabolism. RESULTS: In both sexes, calf cross-sectional muscle area (CSMA) was significantly and independently associated with total bone cross-sectional area (tCSA) and cortical bone cross-sectional area (cCSA) but not with trabecular or cortical volumetric bone mineral density (vBMD). Bioavailable testosterone (Bio-T) was independently associated with both trabecular and cortical vBMD in both sexes. In women, independently of confounders, 25(OH)-vitamin D was positively associated with tCSA and cortical vBMD, while PTH was negatively associated with cortical vBMD. IL-1 beta was negatively correlated with cortical vBMD in women, while TNF-alpha was associated with enhanced bone geometrical adaptation in men. CONCLUSIONS: Physiological parameters that are generically considered risk factors for osteoporosis were associated with specific bone parameters assessed by tibial QCT. Factors known to be associated with increased bone reabsorption, such as 25(OH)-vitamin D, PTH and Bio-T, affected mainly volumetric BMD, while factors associated with bone mechanical stimulation, such as CSMA, affected primarily bone geometry. Our results also suggested that pro-inflammatory cytokines might be considered as markers of bone resorption.

Sarcopenia: age-related skeletal muscle changes from determinants to physical disability.

Human aging is characterized by skeletal muscle wasting, a debilitating condition which sets the susceptibility for diseases that directly affect the quality of life and often limit life span. Sarcopenia, i.e. the reduction of muscle mass and/or function, is the consequence of a reduction of protein synthesis and an increase in muscle protein degradation. In addition, the capacity for muscle regeneration is severely impaired in aging and this can lead to disability, particularly in patients with other concomitant diseases or organ impairment. Immobility and lack of exercise, increased levels of proinflammatory cytokines, increased production of oxygen free radicals or impaired detoxification, low anabolic hormone output, malnutrition and reduced neurological drive have been advocated as being responsible for sarcopenia. It is intriguing to notice that multiple pathways converge on skeletal muscle dysfunction, but the factors involved sometimes diverge to different pathways, thus intersecting at critical points. It is reasonable to argue that the activity of these nodes results from the net balance of regulating mechanisms, as in the case of the GH/IGF-1 axis, the testosterone and cortisol functions, the pro- and anti-inflammatory cytokines and receptors. Both genetic and epigenetic mechanisms operate in regulating the final phenotype, the extent of muscle atrophy and reduction in strength and force generation. It is widely accepted that intervention on lifestyle habits represents an affordable and practical way to modify on a large scale some detrimental outcomes of aging, and particularly sarcopenia. The identification of the molecular chain able to reverse sarcopenia is a major goal of studies on human aging.

Results of anatomic gracilis MPFL reconstruction with precise tensioning.

BACKGROUND: The medial patellofemoral ligament (MPFL) is the most commonly injured structure in patients with objective patellar instability. The objective of this study was to prospectively evaluate the clinical and radiographic results of MPFL reconstruction in 50 patients with chronic patellar instability. METHODS: Fifty patients with chronic patellar instability, aged 15-39 years, were included. The MPFL was reconstructed using a free gracilis autograft tendon. Two anchors were used for patellar fixation, and femoral fixation was achieved with an interference screw placed into a tunnel between the adductor tubercle and medial epicondyle. The graft was tensioned to 10 N with the knee in 30° flexion. IKDC and Kujala scores were assessed pre- and post-operatively. Patellar tilt was measured from CT scans with the quadriceps relaxed and contracted, both pre- and post-operatively. RESULTS: The follow-up period was 7 to 44 months (mean: 25 months, SD 10.3). The mean raw IKDC score increased from 51.5 preoperatively to 71.7 at last follow-up, the mean overall IKDC score increased from 38.5 to 61.7 and the Kujala score increased from 48.3 to 82.4. On CT scans, the mean patellar tilt went from 24° to 16.2° with the quadriceps relaxed and 27.7° to 18.1° in contraction. No recurrent dislocation was observed. CONCLUSION: This technique of MPFL reconstruction provided significant improvements in IKDC and Kujala scores and significant reduction in patellar tilt. No recurrent dislocations were observed during the study period.

Antioxidant profile and early outcome in stroke patients.

BACKGROUND AND PURPOSE: Experimental studies provide evidence of an association between ischemic stroke and increased oxidative stress, but data in humans are still limited and controversial. The purpose of this study was to investigate the time course of plasma antioxidant changes in ischemic stroke patients. METHODS: Plasma antioxidants, including water-soluble (vitamin C and uric acid) and lipid-soluble (vitamins A and E) compounds as well as antioxidant enzyme activities in plasma (superoxide dismutase [SOD] and glutathione peroxidase) and erythrocytes (SOD), were measured by high-performance liquid chromatography (antioxidant vitamins) and by spectrophotometry (antioxidant enzymes) in 38 subjects (25 men and 13 women aged 77.2+/-7.9 years) with acute ischemic stroke of recent onset (<24 hours) on admission, after 6 and 24 hours, and on days 3, 5, and 7. Antioxidant levels in patients on admission were compared with those of age- and sex-matched controls. RESULTS: Mean antioxidant levels and activities in patients on admission were lower than those of controls and showed a gradual increase over time. Patients with the worst early outcome (death or functional decline) had higher vitamin A and uric acid plasma levels and lower vitamin C levels and erythrocyte SOD activity than those who remained functionally stable. CONCLUSIONS: These results suggest that the majority of antioxidants are reduced immediately after an acute ischemic stroke, possibly as a consequence of increased oxidative stress. A specific antioxidant profile is associated with a poor early outcome.

Prednisone and plasma exchange improve suppressor cell function in chronic inflammatory demyelinating polyneuropathy.

We have recently demonstrated that ConA-induced suppressor cell function is defective in chronic inflammatory demyelinating polyneuropathy (CIDP). To assess whether this defect plays a role in disease activity and its reversal is important in recovery, we studied modifications of ConA-induced suppressor cell function induced by prednisone and plasma exchange in 20 patients with CIDP. We found a significant increase towards normal of ConA-induced suppressor cell function after treatment in concurrence with clinical improvement. Induction of suppression, presumably through favorable modifications of the cytokine network or other humoral mediators, might be one, among others, of the mechanisms through which prednisone and plasma exchange are effective in CIDP.

RANTES production and expression is reduced in relapsing-remitting multiple sclerosis patients treated with interferon-beta-1b.

RANTES (regulated upon activation, normal T-cell expressed and secreted), a CC chemokine, appears to play a role in the pathogenesis of relapsing-remitting multiple sclerosis (RR-MS), enhancing the inflammatory response within the nervous system. We have demonstrated that RANTES production is increased in RR-MS compared to controls. Interferon-beta-1b (IFN-beta-1b) treatment reduces RANTES production in sera and peripheral blood adherent mononuclear cell (PBAM) supernatants both in relapse and remission. IFN-beta-1b also reduces RANTES expression in PBAM. Our results suggest that RANTES modulation might represent one of the mechanisms of action of IFN-beta-1b in RR-MS.