Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study.

Despite updating knowledge and a growing number of medications for multiple sclerosis (MS), no definite treatment is available yet for patients suffering from progressive forms of the disease. Autologous bone marrow derived mesenchymal stem cell (BM-MSC) transplantation is a promising method proposed as a therapy for MS. Although the safety of these cells has been confirmed in hematological, cardiac and inflammatory diseases, its efficacy in MS treatment is still under study. Patients with progressive MS (expanded disability status scale score: 4.0 -6.50) unresponsive to conventional treatments were recruited for this study. Twenty-five patients [f/m: 19/6, mean age: 34.7±7] received a single intrathecal injection of ex-vivo expanded MSCs (mean dose: 29.5×10(6) cells). We observed their therapeutic response for 12 months. Associated short-term adverse events of injection consisted of transient low-grade fever, nausea /vomiting, weakness in the lower limbs and headache. No major delayed adverse effect was reported. 3 patients left the study for personal reasons. The mean (SD) expanded disability status scale (EDSS) score of 22 patients changed from 6.1 (0.6) to 6.3 (0.4). Clinical course of the disease (measured by EDSS) improved in 4, deteriorated in 6 and had no change in 12 patients. In MRI evaluation, 15 patients showed no change, whereas 6 patients showed new T2 or gadolinium enhanced lesions (1 lost to follow-up). It seems that MSC therapy can improve/stabilize the course of the disease in progressive MS in the first year after injection with no serious adverse effects. Repeating the study with a larger sample size, booster injections and longer follow-up using a controlled study design is advised.

Multiple sclerosis in Iran: a demographic study of 8,000 patients and changes over time.

BACKGROUND: Iran was formerly considered to be located in a low prevalence zone for multiple sclerosis (MS). During the last decade the number of patients has increased. This study was conducted to estimate the prevalence of MS in the capital city of the country. METHODS: We re-evaluated the files of all patients who had registered at the Iranian Multiple Sclerosis Society during a 10-year period. RESULTS: 8,146 patients (72.3% female, 27.7% male) with a female-to-male ratio of 2.60 had registered. Mean age of disease onset was 27.24 (SD: 8.32). A relapsing-remitting pattern was recognized in 84.9% of the patients. The number of new registrations tripled from 2002 to 2008 and the female-to-male ratio increased from 2 to 3.12. The prevalence of MS in Tehran is estimated to be at least 51.9 per 100,000. Visual impairment was the main presenting symptom. CONCLUSIONS: It seems that the prevalence of MS has increased to a medium-to-high risk level in Iran. The mean age of onset was similar to other studies but the calculated prevalence of early onset MS was increased. The cumulative data indicates that the female-to-male ratio is increasing annually.

IL-2, IFN-gamma, and IL-12 gene polymorphisms and susceptibility to multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease. Positive genetic background could predispose individuals to this chronic disabling disease. In order to investigate the role of some proinflammatory cytokines (interleukin (IL)-2, IL-12, and interferon-gamma (IFN-gamma)) as a risk factor for MS, this study was performed. METHODS: Two hundred and eleven patients with relapsing-remitting form of MS were enrolled in this study and compared with 359 healthy individuals. Using polymerase chain reaction based on sequence-specific primer method, the cytokine genes were amplified, and alleles and genotypes were detected on gel electrophoresis. RESULTS: Significant increases for IFN-gamma AT (+874) genotype (54.5% vs. 37.8%, p = 0.0002) and IL-12 AA (-1188) genotype (60.8% vs. 49.7%, p = 0.014) were found in MS patients in comparison with healthy controls. A significant decrease in IFN-gamma TT (+874) genotype (17.7% vs. 27.5%, p = 0.01) and IL-12 CA (-1188) genotype (30.9% vs. 45%, p = 0.001) in MS patients was also detected. No significant differences of IL-2 G/T (-330) and IL-2 G/T (+166) in alleles and genotypes were observed between MS patients and normal subjects. CONCLUSIONS: It could be suggested that the genetic variation in IL-12 A/C (-1188) and IFN-gamma A/T (+874) cytokine genes could be risk factors for MS patients.

IL-1, IL-1R and TNFalpha gene polymorphisms in Iranian patients with multiple sclerosis.

Different research groups have extensively studied the associations of cytokine gene polymorphisms in different diseases. The role of cytokines gene polymorphisms in multiple sclerosis (MS), as a chronic Immune-mediated neurodegenerative disease, has been previously reported in the various populations. For determining pro-inflammatory cytokine gene polymorphisms, 100 relapsing remitting multiple sclerosis (RRMS) Iranian patients and 140 normal individuals as control enrolled in this study. DNA of each sample was extracted by a modified salting out method. Cytokine single gene nucleotide polymorphisms including IL-1alpha -889, IL-1beta (-511 and +3962), IL-1R pst1 1970, IL-1RA mspal 11100, and TNF-alpha (-308 and -238) were determined by using the PCR-SSP method. The results of our data indicate the decrease in frequency of IL-1alpha TC-889 genotype (p=0.002), IL-1beta TC +3962 genotype (p=0.004), IL-1R T pst1 1970 allele (p= 0.0001), IL-1 RA TC Mspa1 11100 genotype (p=0.009), TNF-alpha A-308 allele (p=0.0002) and AG genotype (p=0.00001) in the patients group versus normal subjects. On the other hand the frequency of IL-1alpha TT -889 genotype (p=0.028), IL-1R C pst1 1970 allele (p=0.0001) and CC genotype (p=0.00006), TNFalpha G -308 allele (p=0.0002) and GG genotype (p=0.000001) decreased significantly in the patients versus normal subjects.These results suggest that polymorphic variations of these pro-inflammatory cytokines may play an important role in susceptibility of Iranian multiple sclerosis patients.

Respiratory rate within the first hour of ascent predicts subsequent acute mountain sickness severity.

BACKGROUND: Altitude illness results from hypobaric hypoxia at altitudes higher than 2500 meters above sea level. To determine whether vital signs can be used as predictors for severe acute mountain sickness, we carried out a prospective observational study. METHODS: A cohort of 90 individuals (male/female ratio: 2; age: 13 - 65 years) in a mountain hotel's clinic at 3450 meters in Iran were studied from September through October 2006. Demographics and vital signs were measured during the first hour of ascent. The individuals were followed for acute mountain sickness symptoms including headache, dizziness, nausea or vomiting, insomnia, and fatigue. Lake Louise criteria were used to diagnose acute mountain sickness. Severe acute mountain sickness was considered if a score of equal or more than 5 was present. Significance was assigned to values of P<0.05. RESULTS: Acute mountain sickness was diagnosed in 34 (37.8%) participants after 24 hours of ascent. Severe acute mountain sickness was detected in 14 (15.6%) participants. A respiratory rate of 20 or more during the first hour of ascent was recorded for nine (64.3%) patients with severe acute mountain sickness and 15 (19.7%) individuals in the negative/mild acute mountain sickness group. This suggests an association between early high respiratory rates and risk of subsequent severe acute mountain sickness (P=0.001). CONCLUSION: There is an association between a rise in the respiratory rate and susceptibility to acute mountain sickness. This can enable us to predict severe acute mountain sickness and prevent it. Furthermore, Tochal Mountain Hotel guests should be aware of the risk of acute mountain sickness and should be recommended to use prophylactic acetazolamide or dexamethasone before ascent.

High-altitude sleep disturbance: results of the Groningen Sleep Quality Questionnaire survey.

OBJECTIVE: To assess the Groningen Sleep Quality Scale (GSQS) for evaluation of high-altitude sleep (HAS) disturbance and employ GSQ questionnaire to describe HAS. METHODS: After the first night's stay at the altitude of 3500 m, quality of sleep for 100 participants (age: 29.13+/-11.01 years; 36 females/64 males) was assessed using the self-administered 15-item GSQS translated into Farsi. RESULTS: Mean GSQS score was 5.36+/-4.32; 38 (38%) participants had a score equal to or less than 2, and 46 (46%) participants had a score equal to or more than 6. A Cronbach's alpha of 0.90 was calculated for internal consistency. Waking up several times during the night was the most prevalent complaint during the first night of sleep, and absolute inability to sleep was the most uncommon problem. CONCLUSIONS: HAS disturbance, which involved many of newcomers to a high altitude, had various harmful effects. For HAS research, GSQS was confirmed to be valid and reliable.

Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study.

BACKGROUND: Mesenchymal stem cells (MSCs) with their potential to differentiate into mesodermal and non-mesodermal lineages have several immunomodulatory characteristics. These properties make them promising tools in cell and gene therapy. OBJECTIVE: To evaluate the potential therapeutic applications of autologous MSC in improving clinical manifestations of MS patients. METHODS: Ten patients were included in this pilot study. All had progressive disease that had not responded to disease modifying agents including Mitoxantrone. Their Expanded Disability Status Scale (EDSS) score ranged from 3.5 to 6. Patients were injected intrathecally with culture expanded MSCs. They were followed with monthly neurological assessment and a MRI scan at the end of the first year. RESULTS: During 13 to 26 months of follow up (mean: 19 months), the EDSS of one patient improved from 5 to 2.5 score. Four patients showed no change in EDSS. Five patients' EDSS increased from 0.5 to 2.5. In the functional system assessment, six patients showed some degree of improvement in their sensory, pyramidal, and cerebellar functions. One showed no difference in clinical assessment and three deteriorated. The result of MRI assessment after 12 months was as following: seven patients with no difference, two showed an extra plaque, and one patient showed decrease in the number of plaques. CONCLUSION: This preliminary report emphasizes on the feasibility of autologous MSC for treatment of MS patients. However, in order to draw a definitive conclusion a larger sample size is required.

Sumatriptan for prevention of acute mountain sickness: randomized clinical trial.

OBJECTIVE: To determine the impact of sumatriptan prophylaxis on acute mountain sickness (AMS) and altitude headache development within 24 hours of ascent, we designed a double-blind, randomized, clinical trial. METHODS: A prospective, double-blind, randomized, placebo-controlled trial was conducted in Tochal Mountain Hotel at an altitude of 3,500 meters above sea level during October 2006 to November 2006. A total of 102 Iranian adults were assigned to receive either sumatriptan succinate (50mg) or placebo within 1 hour of ascent. AMS incidence was measured by Lake Louise AMS score > or = 3 with headache and one other symptom. Secondary outcome measures included severity of syndrome (Lake Louise scores > or = 5), incidence of headache, and severity of headache. RESULTS: Based on intention-to-treat analysis, AMS was more prevalent in placebo group (n = 23 [45.1%]) than sumatriptan group (n = 12 [23.5%]; p = 0.02). Headache also had a greater rate for placebo users (placebo vs sumatriptan group: 29 [56.9%] vs 17 [33.3%]; p = 0.02). No association was detected between sumatriptan prophylaxis and AMS or altitude headache severity. DISCUSSION: Sumatriptan prophylaxis is effective to prevent AMS development. Furthermore, our findings confirm cerebral vasodilative and edematous mechanisms of AMS progression, whereas sumatriptan is a selective 5-hydroxytryptamine(1) receptor subtype agonist and a selective cerebral vasoconstrictor as a result (http://www.controlled-trials.com/ISRCTN87201238/).

Wilson's disease: a great masquerader.

BACKGROUND: Wilson's disease (WD) is a treatable autosomal recessive metabolic disorder which could lead to protean hepatic or neurologic manifestations. WD could mimic many neurologic disorders and is often diagnosed with a long delay. This study describes central nervous system manifestations of a group of Iranian patients with neurologic WD. METHODS: Data from case records of patients with neurologic WD presenting at a referral university hospital and a private clinic in Tehran from 1984 to 2004 were analyzed. RESULTS: Fifty patients from 44 unrelated families with WD were identified, whose mean duration of follow-up was 51.8 (+/-58.5) months. The median age of onset of neurologic symptoms in 37 patients with primary neurologic or simultaneous hepatic-neurologic presentation was 16 (10-38) years, whereas in 13 patients with prior hepatic damage, this was 18.5 (11-34) years. The 6 most common manifestations were dysarthria (80%), drooling (48%), tremor in limbs (44%), abnormal gait (44%), psychiatric and/or sleep symptoms (44%), and dystonia in limbs (42%). CONCLUSION: Neurologic WD has heterogeneous manifestations and should be considered in young patients presenting with dysarthria, drooling, any kind of movement disorders or psychiatric symptoms.

Potential risk factors for diabetic neuropathy: a case control study.

BACKGROUND: Diabetes mellitus type II afflicts at least 2 million people in Iran. Neuropathy is one of the most common complications of diabetes and lowers the patient's quality of life. Since neuropathy often leads to ulceration and amputation, we have tried to elucidate the factors that can affect its progression. METHODS: In this case-control study, 110 diabetic patients were selected from the Shariati Hospital diabetes clinic. Michigan Neuropathic Diabetic Scoring (MNDS) was used to differentiate cases from controls. The diagnosis of neuropathy was confirmed by nerve conduction studies (nerve conduction velocity and electromyography). The multiple factors compared between the two groups included consumption of angiotensin converting enzyme inhibitors (ACEI), blood pressure, serum lipid level, sex, smoking, method of diabetes control and its quality. RESULTS: Statistically significant relationships were found between neuropathy and age, gender, quality of diabetes control and duration of disease (P values in the order: 0.04, 0.04, < 0.001 and 0.005). No correlation was found with any atherosclerosis risk factor (high BP, hyperlipidemia, cigarette smoking). CONCLUSION: In this study, hyperglycemia was the only modifiable risk factor for diabetic neuropathy. Glycemic control reduces the incidence of neuropathy, slows its progression and improves the diabetic patient's quality of life. More attention must be paid to elderly male diabetic patients with poor diabetes control with regard to regular foot examinations and more practical education.

Interferon-gamma gene polymorphism in Iranian patients with multiple sclerosis.

Interferon- gamma (IFN- gamma) is an important immune regulator and inflammatory cytokine which is implicated in the pathogenesis of multiple sclerosis (MS). A single nucleotide polymorphism, T to A, at position +874 in the first intron has previously been shown. This polymorphism is associated with IFN- gamma production level. To study the effect of this polymorphism on susceptibility to multiple sclerosis, we screened genomic DNA samples from clinically definite MS patients and their unaffected first-degree relatives as controls, using sequence-specific primers (PCR-SSP). The results indicated that MS patients showed a lower TT (21.2% vs. 30.3%) and higher AA (21.2% vs. 12.1%) genotypes compared to controls, although there were statistically no differences in the IFN- gamma genotype distribution between these two groups. Thus, our data indicate that there is no association between IFN- gamma +874 polymorphism and MS susceptibility or severity of the disease.

Academic achievement and learning abilities in left-handers: guilt or gift?

The main purpose of this cross-sectional study was to compare the acceptance rate (AR) of left-handers (LHs) with that of right-handers (RHs) in the college entrance examination (CEE) for the national universities in Iran. During 5 successive years, fifty thousand participants in this exam were randomly sampled. We evaluated the relationships between AR and hand preference, sex, college admission (CA), entrance exam score (EES) and study areas: Mathematics, Natural Sciences, Humanities and Art. The acceptance rate of the LHs over the entire study period was significantly higher than that of the RHs (27.3% versus 24.3%, p < 0.0001). The mean score attained on examination by LHs was significantly higher than that of RHs in all study areas (p < 0.002). The acceptance rate of LHs in all study areas was higher but the difference reached statistical significance in the Art area only (p < 0.01). It is concluded that left-handers may be regarded as a heterogeneous large group consisting of different subgroups. Those who are able to compete for the college entrance examination score are even more successful than right-handers in terms of average EES and the rate of CA.