Multiple sclerosis (MS) is an autoimmune disease triggered by a combination of genetic and environmental risk factors which are however individually insufficient to provoke the disease. Previous investigations studied the coexistence of cancer in MS patients, and only a few relations between the geographic distribution of MS and that of cancer. The aim of this research was to find an environmental link between the aetiology of MS and cancers in Croatia. Incidence and prevalence of MS in Croatia were compared with the incidence of the most frequent cancer sites: stomach cancer, cancer of the colon and the rectum, pancreatic cancer, lung cancer, cancer of the kidneys and brain cancer. Data for MS were collected from seven population-based epidemiologic studies which used Poser's diagnostic criteria and reported the number of cases and the magnitude of the studied population. Data for cancers were drawn from the Croatian National Cancer Registry. The analysis was done for single municipalities, grouped in their belonging regions or counties, and separately for the continental and the coastal area. For each rate a 95% confidence interval was calculated. The differences between rates were tested with the chi-square test as well. In addition, MS incidence or prevalence were correlated with the corresponding cancer incidence data. Pearson's correlation coefficients were used to measure the correlation between both diseases. Calculations were done with the statistical package Statistica V 7.1. and the Smith's Statistical Package freeware In the continental area of Croatia the mean annual incidence (per 100,000 inhabitants) of MS was nearly two folds higher than in the coastal area: 2.1 vs. 1.3 (p = 0.0029). The difference was lower when expressed by prevalence: 46.5 vs. 36.7 (p = 0.0601). Among the malignant neoplasms, in the continental area significantly higher incidence rates were found for stomach (32.9 vs. 20.8; p = 3.14E-14) and lung cancer (55.8 vs. 46.4; p = 1.21E-05), whilst colon cancer alone (20.4 vs. 15.7; p = 9.44E-05) or colorectal cancer (38.3 vs. 31.6; p = 8.18E-05) had a significantly higher incidence in the coastal area. The geographic distribution of MS expressed by incidence was significantly correlated with pancreatic (r = 0.62024, df=23, p = 0.00094) and lung cancer (r = 0.46380, df=23, p = 0.01953). This research adds further malignant neoplasms, possibly exposure-related, to the list of diseases with geographic distribution like MS. The similarity of MS distribution with the named malignancies is unlikely to be incidental. MS in Gorski Kotar and Slavonia seems to be associated with a diet rich in meat and fat. A diet rich in fat and meat and poor in vegetables is a risk factor for stomach, colorectum, pancreatic as well as lung cancers. Some authors have documented a possible protective role of the "Mediterranean diet" for the named cancers. Olive oil is the main source of fat in the "Mediterranean diet". Oleocanthal, aphenolic compound of the extra-virgin olive oil was found to inhibit the cyclooxigenase enzymes which are involved in demyelination and tumorigenesis. We hypothesize that the "Mediterranean diet", olive oil and particularly oleocanthal, to have a protective role in MS too.

BACKGROUND:Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activi-ties and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.

OBJECTIVE:Aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.

METHOD:Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclu-sion of studies on neuropsychiatric disorders.

RESULTS:Laboratory and clinical studies on the potential role of CBD in Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.

CONCLUSIONS:Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.

Subsequent to EMA approval of tetrahydrocannabinol (THC): cannabidiol (CBD) oromucosal spray based on results of various studies, including an enriched-design clinical trial, two newer postapproval randomized trials have confirmed its efficacy and safety for treating resistant multiple sclerosis spasticity, while simultaneously addressing specific authorities' concerns. A double-blind, placebo-controlled, Phase IV trial, conducted as part of the EMA's risk management plan, found no effect of THC:CBD spray on cognition and mood after 50 weeks of treatment. In the Sativexas add-on therapy versus further optimized first-line ANTispastics (SAVANT)  study, add-on THC:CBD spray was significantly more effective than readjusting standard antispasticity therapy and provided new evidence of efficacy as requested by German authorities. SAVANT results support practical recommendations for treating resistant multiple sclerosis spasticityin daily practice.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) caused by demyelination, immune cell infiltration, and axonal damage. Herein, we sought to investigate the influence of physical exercise on mice experimental autoimmune encephalomyelitis (EAE), a reported MS model. Data show that both strength and endurance training protocols consistently prevented clinical signs of EAE and decreased oxidative stress, an effect which was likely due to improving genomic antioxidant defense-nuclear factor erythroid 2-related factor (Nrf2)/antioxidant response elements (ARE) pathway-in the CNS. In addition, physical exercise inhibited the production of pro-inflammatory cytokines interferon (IFN)-γ, interleukin (IL)-17, and IL-1β in the spinal cord of mice with EAE. Of note, spleen cells obtained from strength training group incubated with MOGshowed a significant upregulation of CD25 and IL-10 levels, with a decrease of IL-6, MCP-1, and tumor necrosis factor (TNF)-α production, mainly, during acute and chronic phase of EAE. Moreover, these immunomodulatory effects of exercise were associated with reduced expression of adhesion molecules, especially of platelet and endothelial cell adhesion molecule 1 (PECAM-1). Finally, physical exercise also restored the expression of tight junctions in spinal cord. Together, these results demonstrate that mild/moderate physical exercise, when performed regularly in mice, consistently attenuates the progression and pathological hallmarks of EAE, thereby representing an important non-pharmacological intervention for the improvement of immune-mediated diseases such as MS. Graphical Abstract Schematic diagram illustrating the beneficial effects of physical exercise during experimental model of MS. Physical exercise, especially strength (ST) and endurance (ET) training protocols, inhibits the development and progression of disease, measured by the mean maximal clinical score (1.5 and 1.0, respectively), with inhibition of 30 % and 50 %, respectively, based on the AUC, compared with EAEuntreated group. In addition, ST and ET decreased oxidative stress, possibly, through genomic antioxidant defense, Nrf2-Keap1 signaling pathway, in the CNS. Physical exercise inhibited the production of inflammatory cytokines, such as IFN-γ, IL-17 and IL-1β in the spinal cord after EAE induction, as well as spleen cells obtained from ST group showed a significant upregulation of regulatory T cell markers, such as CD25 andIL-10 levels, and blocked IL-6, MCP-1 and TNF-α production, mainly, during acute and chronic phase of EAE. Finally, these immunomodulatory effects of exercise were associated with inhibition of adhesion molecules and reestablishment of tight junctions expression in spinal cord tissue, thereby limiting BBB permeability and transmigration of autoreactive T cells to the CNS. NO, nitric oxide; GPx, glutathione peroxidase, GSH, glutathione; Nrf2, nuclear factor (erythroid-derived 2)-like 2; CNS, central nervous system; BBB, blood-brain barrier; IFN-g, interferon-gamma; IL-17, interleukin 17; IL-1b, interleukin-1beta.

Background: Colonic microbiome is thought to be involved in auto-immune multiple sclerosis (MS). Interactions between diet and the colonic microbiome in MS are unknown.

Methods: We compared the composition of the colonic microbiota quantitatively in 25 MS patients and 14 healthy controls.Fluorescence in situ hybridization (FISH) with 162 ribosomal RNA derived bacterial FISH probes was used. Ten of the MS patients received a ketogenic diet for 6 months. Changes in concentrations of 35 numerically substantial bacterial groups were monitored at baseline and at 2, 12, and 23/24 weeks.

Results: No MS typical microbiome pattern was apparent.The total concentrations and diversity of substantial bacterial groups were reduced in MS patients (P<0.001). Bacterial groups detected with EREC (mainly Roseburia), Bac303 (Bacteroides), and Fprau (Faecalibacterium prausnitzii) probes were diminished the most. The individual changes were multidirectional and inconsistent. The effects of a ketogenic diet were biphasic. In the short term, bacterial concentrations and diversity were further reduced. They started to recover at week 12 and exceeded significantly the baseline values after 23-24 weeks on the ketogenic diet.

Conclusions: Colonic biofermentative function is markedly impaired in MS patients.The ketogenic diet normalized concentrations of the colonic microbiome after 6 months.

Multiple sclerosis (MS) is a progressive condition affecting the central nervous system (CNS), and is characterized by the development of demyelinated lesions and plaques in the brain and spinal cord. Exercise is beneficial against dementia in elderly patients, so we investigated the effects of exercise on memory in relation to hippocampal demyelination and neuroplasticity in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]). Mice were randomly divided into three groups: Sham, EAE, and EAE and exercise (EAE+EX). EAE+EX mice exercised five times a week for 4weeks, and all mice performed step-down avoidance tasks in order to verify memory ability. We analyzed changes in myelin basic protein (MBP), 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNPase), 5-bromo-2'-deoxyuridine (brdU), doublecortin (DCX), bcl-2, bax, TUNEL, caspase-3, and brain derived neurotrophic factor (BDNF) via immunoassay or histological staining. We found decreased memory ability in EAE mice, accompanied by impaired myelination, increased apoptosis and cell proliferation, and decreased BDNF in the hippocampus. The memory decline and changes in demyelination, apoptosis, BDNF, and cell proliferation were partially reversed in EAE+EX mice. Our findings suggest that in patients with MS, regular exercise may benefit cognitive function by rescuing some hippocampal cellular and molecular impairments.

Since it was discovered that UV radiation was the main environmental cause of skin cancer, primary prevention programs have been started. These programs advise to avoid exposure to sunlight. However, the question arises whether sun-shunning behaviour might have an effect on general health. During the last decades new favourable associations between sunlight and disease have been discovered. There is growing observational and experimental evidence that regular exposure to sunlight contributes to the prevention of colon-, breast-, prostate cancer, non-Hodgkin lymphoma, multiple sclerosis, hypertension and diabetes. Initially, these beneficial effects were ascribed to vitamin D. Recently it became evident that immunomodulation, the formation of nitric oxide, melatonin, serotonin, and the effect of (sun)light on circadian clocks, are involved as well. In Europe (above 50 degrees north latitude), the risk of skin cancer (particularly melanoma) is mainly caused by an intermittent pattern of exposure, while regular exposure confers a relatively low risk. The available data on the negative and positive effects of sun exposure are discussed. Considering these data we hypothesize that regular sun exposure benefits health.

Background:Low vitamin D and/or sun exposure have been associated with increased risk of multiple sclerosis (MS) onset. However, comparatively, few studies have prospectively examined associations between these factors and clinical course.

Objectives:To evaluate the association of sun exposure parameters and vitamin D levels with conversion to MS and relapse risk in a prospectively monitored cohort of 145 participants followed after a first demyelinating event up to 5-year review (AusLong Study).

Methods:Sun exposure prior to and after onset measured by annual questionnaire; ultraviolet radiation (UVR)"load"estimated by location of residence over the life course and ambient UVR levels. Serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at baseline, 2/3-year, and 5-year review. MS conversion and relapse assessed by neurologist assessment and medical record review.

Results:Over two-thirds (69%) of those followed to 5-year review (100/145) converted to MS, with a total of 252 relapses. Higher pre-MS onset sun exposure was associated with reduced risk of MS conversion, with internal consistency between measures and dose-response relationships. Analogous associations were also seen with risk of relapse, albeit less strong. No consistent associations were observed between postonset sun exposure and clinical course, however. Notably, those who increased their sun exposure during follow-up had significantly reduced hazards of MS conversion and relapse. Serum 25(OH)D levels and vitamin D supplementation were not associated with conversion to MS or relapse hazard.

Conclusion:We found that preonset sun exposure was protective against subsequent conversion to MS and relapses. While consistent associations between postonset sun exposure or serum 25(OH)D level and clinical course were not evident, possibly masked by behavior change, those participants who markedly increased their sun exposure demonstrated a reduced MS conversion and relapse hazard, suggesting beneficial effects of sun exposure on clinical course.

BACKGROUND:Due to the chronic character of multiple sclerosis (MS), non-pharmacological treatment can be applied. These therapies can be a good complementation to standard pharmacological treatment.

OBJECTIVES:The aim of the study was to evaluate the effectiveness of whole-body cryotherapy (WBC) and physical exercise training on the psychological and general well-being of patients with MS.

MATERIAL AND METHODS:The study was carried out on 60 patients, who were divided into 3 groups: cryotherapy (Cryo), physical exercise training (Gym) and cryotherapy with physical exercise training (CryoGym). The Psychological General Well-Being Index, the Hospital Anxiety and Depression Scale and the Rivermead Mobility Index were used at 2 points in time: T1 - before the first therapy session and T2 - after 14 days of therapy.

RESULTS:Statistically significant differences in the psychosocial well-being were found in the Gym and CryoGym group. Reduction of depressive symptoms and improved functional status was noted in Cryo group. The most significant improvement was observed in the group using WBC with exercise training (CryoGym).

CONCLUSIONS:Whole-body cryotherapy with physical exercise training was an effective therapy for patients with MS. The introduction of WBC into the standard physiotherapy protocol for patients with MS is fully justified.

BACKGROUND:Spinal cord injury (SCI) and multiple sclerosis (MS) are associated with increased risks of depression. Acute exercise may improve mood in these populations via its affect on inflammation.

OBJECTIVE:To determine if acute exercise can positively affect mood in individuals with SCI and MS, and whether exercise-induced changes in inflammation contribute to such improvements.

METHODS:Thirteen participants completed 30 minutes of moderate-intensity exercise. Mood data (POMS questionnaire) and blood samples were taken before and after exercise, and blood was analyzed for inflammatory mediators and kynurenine pathway metabolites.

RESULTS:There was a significant reduction in total mood disturbance (TMD) pre to post-exercise, and pre to one-hour post-exercise. There was a significant decrease in TNF-α from pre to post-exercise, with further reductions one-hour post-exercise. There were no correlations between changes in TMD and changes in inflammation. However, changes in certain cytokines showed significant or trending correlations with changes in subsets of the POMS. Likewise, there was a trend for a correlation between exercise-induced changes in KYN/TRP and depression (p = 0.096).

CONCLUSIONS:Acute exercise can positively affect mood after SCI and MS, and this change may be partially accounted for by exercise-induced changes in inflammation. This relationship may be, in part, kynurenine pathway-dependent.

BACKGROUND:Pilates is an exercise method which increases strength and endurance of core muscles and improves flexibility, dynamic postural control and balance.

OBJECTIVE:To analyze and compare the effects of Mat and Reformer Pilates methods in Patients with Multiple Sclerosis (MS).

METHODS:Thirty-eight patients with MS were included in the study. Participants were randomly divided into 3 groups as Mat Pilates, Reformer Pilates and control groups. The subjects in the Pilates groups did Mat or Reformer Pilates for 8 weeks, 2 days a week. The control group did breathing and relaxation exercises at home. Balance, functional mobility, core stability, fatigue severity and quality of life were evaluated.

RESULTS:Balance, functional mobility, core stability, fatigue severity and quality of life improved after Pilates in Mat and Reformer Pilates groups (p < 0.05). On the other hand, we could not find any changing in the control group (p > 0.05). When the gain obtained in the Pilates groups is compared, it has been observed that progress has been more in trunk flexor muscle strength in the Reformer Pilates group (p < 0.05) and that the gain has been similar in the other parameters (p > 0.05).

CONCLUSIONS:As a result, patients with MS have seen similar benefits in Reformer Pilates and Mat Pilates methods.

Oxidative stress is an important factor which contribute to the pathogenesis of lesions in multiple sclerosis (MS). Whole body cryotherapy (WBCT) is often used in treatment neurological and orthopedic diseases.

THE AIM, MATERIAL AND METHODS: The aim of this study was to determinate the level of total antioxidative status (TAS) in plasma and activity of superoxide dismutase (SOD) and catalase (CAT) in erythrocytes of MS patients (n = 28) before and after 10 exposures of WBCT (-120 degrees C/3 minutes/day). 16 MS patients during 10 exposures of WBCT additionally were supplemented by 10 mg of melatonin.

RESULTS: Increasing of TAS level in plasma as well as supplemented with melatonin and non-supplemented MS patients was observed after 10 exposures of WBCT Melatonin statistically significant increased activity of SOD and CAT in erythrocytes of MS patients treated with WBCT.

CONCLUSIONS: Results of our study indicate significant increase of TAS level in plasma of MS patients of WBCT treatment. This indicate that WBCT might be a therapy which suppress oxidative stress in MS patients.

AIM: This paper is a report of a systematic review to evaluate the efficacy of reflexology in any condition. BACKGROUND: Anecdotal evidence has shown potential benefits of reflexology in a variety of health conditions. However, the efficacy of reflexology has yet to be determined. DATA SOURCES: Cochrane library, PubMed, MEDLINE, EBM review, ProQuest Medical Bundle and SCOPUS databases were searched using the following medical subject headings or key words: reflexology, foot reflexotherapy, reflexological treatment, foot massage and zone therapy. Chinese articles were searched through the Chinese electronic periodical services and Wangfane database. The publication date was limited from 1996 to 2007. REVIEW METHODS: Studies were selected if they were written in English or Chinese, used a controlled clinical trial design, used reflexology as a stand-alone modality, and reported such outcomes as symptoms relief, quality of life and patients' perceptions of reflexology. Study quality was reviewed based on the evidence rating system of the United States Preventive Services Task Force, and studies with the evidence rating of II-2 fair or above were included in this review. RESULTS: Among the five studies suitable for review, there was only one report of a statistically significant treatment effect. Among the 12 outcome variables examined, the treatment effect size for urinary symptoms was large, whereas the effect size for other conditions was negligible. CONCLUSION: There is no evidence for any specific effect of reflexology in any conditions, with the exception of urinary symptoms associated with multiple sclerosis. Routine provision of reflexology is therefore not recommended.

AIM: This paper is a report of a systematic review to evaluate the efficacy of reflexology in any condition. BACKGROUND: Anecdotal evidence has shown potential benefits of reflexology in a variety of health conditions. However, the efficacy of reflexology has yet to be determined. DATA SOURCES: Cochrane library, PubMed, MEDLINE, EBM review, ProQuest Medical Bundle and SCOPUS databases were searched using the following medical subject headings or key words: reflexology, foot reflexotherapy, reflexological treatment, foot massage and zone therapy. Chinese articles were searched through the Chinese electronic periodical services and Wangfane database. The publication date was limited from 1996 to 2007. REVIEW METHODS: Studies were selected if they were written in English or Chinese, used a controlled clinical trial design, used reflexology as a stand-alone modality, and reported such outcomes as symptoms relief, quality of life and patients' perceptions of reflexology. Study quality was reviewed based on the evidence rating system of the United States Preventive Services Task Force, and studies with the evidence rating of II-2 fair or above were included in this review. RESULTS: Among the five studies suitable for review, there was only one report of a statistically significant treatment effect. Among the 12 outcome variables examined, the treatment effect size for urinary symptoms was large, whereas the effect size for other conditions was negligible. CONCLUSION: There is no evidence for any specific effect of reflexology in any conditions, with the exception of urinary symptoms associated with multiple sclerosis. Routine provision of reflexology is therefore not recommended.

v is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years.

[n/a]