Osteogenic differentiation of skeletal muscle progenitor cells is activated by the DNA damage response.

Heterotopic ossification (HO) is a pathological condition characterized by the deposition of mineralized tissue in ectopic locations such as the skeletal muscle. The precise cellular origin and molecular mechanisms underlying HO are still debated. In our study we focus on the differentiation of mesoangioblasts (MABs), a population of multipotent skeletal muscle precursors. High-content screening for small molecules that perturb MAB differentiation decisions identified Idoxuridine (IdU), an antiviral and radiotherapy adjuvant, as a molecule that promotes MAB osteogenic differentiation while inhibiting myogenesis. IdU-dependent osteogenesis does not rely on the canonical BMP-2/SMADs osteogenic pathway. At pro-osteogenic conditions IdU induces a mild DNA Damage Response (DDR) that activates ATM and p38 eventually promoting the phosphorylation of the osteogenesis master regulator RUNX2. By interfering with this pathway IdU-induced osteogenesis is severely impaired. Overall, our study suggests that induction of the DDR promotes osteogenesis in muscle resident MABs thereby offering a new mechanism that may be involved in the ectopic deposition of mineralized tissue in the muscle.

Effects of interferon beta-1a and -1b over time: 6-year results of an observational head-to-head study.

OBJECTIVE: To evaluate and compare the long-term efficacy and safety of two different beta-interferon preparations (IFN-beta-1a vs IFN-beta-1b). MATERIALS AND METHODS: Two parallel outpatient groups with relapsing-remitting multiple sclerosis (RRMS), according to Poser criteria, were treated with either intramuscular IFN-beta-1a 30 microg (group A, n = 62) or subcutaneous IFN-beta-1b 250 microg (group B, n = 64). RESULTS: A statistically significant reduction was seen in the relapse rate (P < 0.0001) in both groups. No significant difference was found between the two groups (P = 0.43). After 6 years of therapy, the mean Expanded Disability Status Scale score was 3.22 +/- 1.47 (delta 1.03 +/- 1.35) in group A and 3.34 +/- 1.47 (delta 0.97 +/- 1.47) in group B (P = 0.47). CONCLUSIONS: Our study results suggest that the efficacy of IFN-beta-1a 30 microg once weekly and SC IFN-beta-1b 250 microg every other day is similar. Both IFN-beta-1a and IFN-beta-1b are effective in slowing disability progression.

Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients. Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.

Long-term survival of Parkinson's disease: a population-based study.

In a set of a population- based study, long-term survival of 59 prevalent PD patients was compared with that of individuals free of neurological diseases matched 1:2 by sex and age of enrolment. PD individuals, compared with reference subjects, showed a two-fold increased risk of death (OR 2.1; 95 % CI 1.4, 3.1). Among causes of death, pneumonia and cachexia were significantly more frequent among PD patients than among individuals free of neurological diseases. We confirmed in a long-term follow-up study an increased mortality among PD individuals compared with that of the general population.

Possible increasing risk of multiple sclerosis in Catania, Sicily.

OBJECTIVE: To update prevalence and incidence rates of multiple sclerosis (MS) in Catania, Italy during 1990 to 1999 and evaluate their temporal profiles to assess a possible increase in the MS risk in our study population. METHODS: We studied the frequency of MS in Catania, Italy (population of 313,110 as reported in the 2001 census). The primary sources for the case ascertainment were the neurologic and motor-rehabilitation departments, the MS centers, the Italian MS Association, private neurologists, and family doctors. We considered as prevalent and incident cases all patients who satisfied Poser's criteria for clinically definite MS (CDMS), laboratory-supported definite MS (LSDMS), clinically probable MS (CPMS), and laboratory-supported probable MS (LSPMS). RESULTS: We found 288 subjects with MS who had onset of disease before December 31, 1999 (prevalence day) in a population of 313,110 inhabitants. The prevalence rate was 92.0/100,000 (95% CI 81.8 to 103.2) and was higher in women (102.4/100,000) than in men (80.4/100,000). The age-specific prevalence showed a peak in the group aged 35 to 44 years (208.2/100,000). From 1990 to 1999, 155 patients with MS had the clinical onset of the disease. The mean annual incidence was 4.7/100,000 (95% CI 4.0 to 5.5). Age-specific incidence showed a peak in the group aged 25 to 34 years (11.7/100,000). Mean annual incidence for 5-year intervals increased from 3.9/100,000 during 1990 to 1994 to 5.5/100,000 during 1995 to 1999. CONCLUSIONS: Prevalence and incidence rates of multiple sclerosis have further increased during the last decade.

Brain atrophy and lesion load in a large population of patients with multiple sclerosis.

OBJECTIVE: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. METHODS: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). RESULTS: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. CONCLUSIONS: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

[Spasticity in multiple sclerosis]. / Spasticità e sclerosi multipla.

Already in 1860, the great neurologist Charcot described the symptom spasticity in patients affected by "sclerose en plaque". Spasticity is one of the most common symptoms of multiple sclerosis MS). The consequences of spasticity are very disadvantages because it hinders the functional mobility and overburden disability. Moreover, in the later stages of MS spasticity may be complicated by seating problems, pressure sores, fibrous contractures and poor perineal hygiene. In this article, the therapeutical management of MS spasticity, in all its components (pharmacological, rehabilitative, surgical) is reviewed.

[Management of neuropathic bladder in multiple sclerosis]. / Management della vescica neurologica nella sclerosi multipla.

It is estimated that almost 70% of patients affected by multiple sclerosis (MS) suffer from urinary symptoms, with devastant impact on Quality of Life (QoL). The major aims of management should be to ameliorate the patients quality of life and to prevent the frequent complications of bladder dysfunction such as infention and renal damage. Therapy can usually eliminate or reduce the symptoms of neuropathic bladder. In the following pages is discussed the complex management of urinary symptoms in MS patients.

[Neuroprotective effects of topiramate]. / Effetti neuroprotettivi del topiramato.

Topiramate (TPM) is a new anti-convulsant drug, prescribed in epileptic seizure. Pharmacological actions of TPM are: a) a positive modulation of GABA receptors; b) inhibition of the kainite and aminohydroxymethylisoxazole propionic acid (AMPA) glutamate receptor sub-types; c) a use-dependent Na+ channel blocker. Recent studies suggest that TPM can have anti-excitotoxic properties, because it protects against motor neuron degeneration. Moreover, TPM enhances neuroprotection and reduces hemorrhagic incidence in focal cerebral ischemia.

[Symptomatic management in multiple sclerosis]. / Aspetti sintomatici della sclerosi multipla.

Multiple sclerosis is an autoimmune disease, characyerized by demylinization of white matter of Central Nervous System (CNS). Its etiology is still unknown. In the world, about 2.000.000 of people are affected by MS, with higher prevalence in North-America and North-Europe. Two are the essential features of the therapeutical management in MS: 1) immunomodulating therapy, which consists of "disease modifing drugs"; 2) symptomatic treatment. Only some patients can benefit of immunomodulating therapy, whereas symptomatic treatment can be helpfull to everbody. In the following pages the authors will review the medical options used in the diagnostic, prognostic and therapeutic management of MS.

An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients.

We amplified sequences of the Chlamydia pneumoniae (CP) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P = 0.00022). CP+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P = 0.02) compared to CP- MS patients and tended to have an anticipation of age at disease onset (32.3 +/- 12 versus 28.5 +/- 10 years; P = ns) causing a longer disease duration (7.5 +/- 5 versus 4.4 +/- 4 years; P = 0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that CP infection of the central nervous system (CNS) might affect disease course in a subgroup of MS patients.

Prevalence of Parkinson's disease: a door-to-door survey in rural Bolivia.

A door-to-door survey was carried out in rural areas of the Cordillera Province, Bolivia, to determine the prevalence of Parkinson's diseases (PD) in a sample of 9955 subjects. We found five cases of PD on prevalence day, November 1, 1994. The crude prevalence was 50.2/100,000 (95% CI 18.5-124.5) and 286/100,000 (95% CI 28-543) in subjects aged 40 years or more. Our prevalence is close to rates found in other in developing countries.

Epilepsy, cysticercosis, and toxocariasis: a population-based case-control study in rural Bolivia.

OBJECTIVE: To assess the relationship between epilepsy and infection with Taenia solium and Toxocara canis with a case-control study, in the rural area of the Cordillera Province, Bolivia. METHODS: A preliminary two-phase door-to-door prevalence survey determined the prevalence of epilepsy and identified cases and control subjects. At least two control subjects per case were selected, matching on sex, age, and community of residence. Cases and control subjects were assessed serologically for antibodies against T. canis by ELISA and against T. solium by enzyme-linked immunoelectrotransfer blot (EITB). RESULTS: The prevalence survey found 130 confirmed cases of epilepsy, of which 113 were eligible for the case-control study (59 partial seizures and 54 generalized seizures). Two hundred thirty-three control subjects were selected. Multivariable analysis for a matched case-control study was carried out. There was an association between EITB positivity for T. solium and epilepsy with an OR of 1.85 (95% CI 0.99 to 3.4) for all cases. A stronger association was found in those with partial epilepsy with a late onset of disease (15 years and older), where the OR was 3.66 (95% CI 1.10 to 12.10). A positive association was also found with T. canis for all cases with an OR of 2.70 (95% CI 1.41 to 5.19). This increased for those with late-onset partial epilepsy to an OR of 18.22 (95% CI 2.10 to 158.10). CONCLUSION: This finding suggests that both neurocysticercosis and toxocariasis may in part explain the higher prevalence of epilepsy, particularly partial epilepsy, in developing countries.

Lifetime prevalence of Bell's palsy in rural Bolivia: a door-to-door survey.

We carried out a door-to-door survey in rural areas of the Cordillera Province, Bolivia, to determine the prevalence of the most common neurological diseases in a sample of about 10,000 inhabitants. A team of non-doctor health workers administered a standard screening instrument for neurological diseases, a slightly modified version of the World Health Organization protocol. All subjects found positive at the screening phase underwent a complete neurological examination. On screening, we found 1,130 positive subjects, of whom 909 were aged 15 years and above. After the neurological examination, we found 52 cases who had experienced Bell's palsy during their life in the population aged 15 years and above. The lifetime prevalence on November 1, 1994 was 11.1/1,000 (95% confidence interval 7.8-14.5) for the population aged 15 years and above. The prevalence was higher in women than in men (13.7 and 8.7/1,000, respectively) and increased with age, reaching a peak in the group aged 65 years or more (31.7/1,000). Only 3 cases (5.8%) had received medical therapy.

[Neurogenic dysphagia: physiology, physiopathology and rehabilitative treatment]. / La disfagia in neurologia: fisiologia, fisiopatologia e trattamento riabilitativo.

Swallowing is both a voluntary than a reflex function. It consist in transporting feeding from mouth to the stomach. Swallowing function occurs with very frequency during the day and needs complex neuromuscular coordination. Several neurologic diseases determine swallowing disorders. Dysphagia, is the difficulty in swallowing. In slight disorders, swallowing function is sufficiently compensated, symptoms are few or absent. Sometimes the patient is able to compensate and obtains a safe deglutition. Rehabilitation of swallowing disorders is based on the assessment of all symptoms and troubles causing dysphagia and on the improvement of the specific disabilities. Rehabilitation is aimed to make patient able for a safe oral feeding. We can use classic specific physiotherapy, compensatory movements of head and neck, electrostimulation, and the chemical myotomia by botulinum toxin injection.

Interferon beta and multiple sclerosis: look at the evidence.

Recent advances in therapy for multiple sclerosis (MS) have centred on the use of the disease-modifying drugs glatiramer acetate (GA) and interferon (IFN) beta. Several large-scale clinical trials have been carried out on the use of these compounds, but there have been few studies that have directly compared their efficacy in MS. Furthermore, there has been controversy and confusion over the IFN beta therapy regimen that will achieve the best possible clinical outcome for MS patients. This review focuses principally on clinical trials of IFN beta-1a, where data that allow direct comparison of different treatment regimens are now available. Current data indicate that IFN beta, and in particular IFN beta-1a, has important advantages over GA in the treatment of relapsing-remitting MS (RRMS). Additionally, IFN beta-1a (Rebif, Serono), 44 microg administered subcutaneously (s.c.) three times weekly (t.i.w.), is significantly more effective than IFN beta-1a (Avonex, Biogen), 30 microg administered intramuscularly once weekly. For optimal management of RRMS, treatment with IFN beta-1a, 44 microg s.c. t.i.w., should begin as early as possible after diagnosis.

Door-to-door prevalence survey of epilepsy in three Sicilian municipalities.

A door-to-door prevalence survey of epilepsy was conducted in 3 Sicilian municipalities, as of November 1, 1987. In phase 1, the screening by questionnaire of 24,496 eligible subjects (participation = 92%) identified 544 suspected to have epilepsy. In phase 2, neurological evaluation of the 544 subjects yielded 111 with epilepsy. Of the 111 subjects, 103 (93%) had been previously diagnosed, 68 (61%) were taking antiepileptic medication, and 81 (73%) had active epilepsy. Referring to the 81 subjects with active epilepsy, the seizure type was generalized in 60 (74%), partial in 19 (23%) and undetermined in 2 (3%). The prevalence of active epilepsy (per 1,000 population) was 3.3 overall, 3.5 for men and 3.2 for women. The age-specific patterns for active epilepsy differed by sex, with higher figures for men at younger ages (5-19 years) and older ages (50-99 years). The age-specific prevalence figures for active epilepsy were lower than those from previous Italian surveys.

Combination of cyclophosphamide and interferon-beta halts progression in patients with rapidly transitional multiple sclerosis.

The effects of combined treatment with cyclophosphamide (CTX) and interferon-beta (IFN-beta) are described in selected patients with "rapidly transitional" multiple sclerosis. This form of multiple sclerosis is extremely active with very frequent and severe attacks which produce a dramatic increase on the expanded disability status scale (EDSS). Ten patients with rapidly transitional multiple sclerosis were previously treated with interferon-beta, but none benefited by this treatment. Monthly treatment with intravenous CTX, from 500 mg/m(2) to 1500 mg/m(2) to obtain a chronic lymphocytopenia (600/mm(3) to 900/mm(3)) produced a marked and significant reduction in the number of relapses (p<0.0001), disability previously accumulated (p<0.0001), and a reduction of T2 MRI burden of lesion. This particular group of patients benefited by combining cyclophosphamide and IFN-beta. The possibility is considered of carrying out further studies to test the efficacy of the association between the two drugs for patients who are not responsive to IFN-beta or other active disease modifying therapies.

Increased serum levels of interleukin-18 in patients with multiple sclerosis.

Serum but not CSF concentrations of the interferon-gamma-inducing cytokine interleukin (IL)-18 were significantly augmented in patients with MS as compared to both healthy controls and patients with other neurologic diseases. Patients with MS with secondary chronic progressive disease had significantly higher serum levels than those with relapsing remitting MS. In the latter group, IL-18 levels were higher in patients with acute exacerbation as compared to those with stable disease.

Sodium fusidate (fusidin) ameliorates the course of monophasic experimental allergic encephalomyelitis in the Lewis rat.

We have evaluated the effect of the immunosuppressant sodium fusidate (fusidin) on the course of acute monophasic experimental encephalomyelitis (EAE) in male Lewis rats. Prophylactic treatment with fusidin, 80 or 120 mg/kg bd wt., markedly ameliorated the course of the disease in rats immunized with myelin basic proteins in complete Freund's adjuvant, entailing delayed onset of symptoms, lower clinical scores and more rapid recovery than PBS-treated control rats. The fusidin-treated, immunized rats exhibited milder mononuclear cell infiltration of brains and spinal cords than control animals. These data provide further evidence for the anti-inflammatory effect of fusidin and suggest that this drug may be valuable for the treatment of human multiple sclerosis.