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Background and purpose: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). Methods: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. Results: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). Conclusions: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

Objective To assess sleep characteristics and the occurrence of abnormal muscle activity during sleep, such as REM sleep without atonia (RSWA), REM sleep behavior disorder (RBD), and periodic leg movements during sleep (PLMS), in patients with amyotrophic lateral sclerosis (ALS). Methods A total of 41 patients with ALS and 26 healthy subjects were submitted to clinical interview and overnight video-polysomnography. Results A total of 22 patients with ALS (53.6%) reported poor sleep quality. Polysomnographic studies showed that patients with ALS had reduced total sleep time, increased wakefulness after sleep onset, shortened REM and slow-wave sleep, and decreased sleep efficiency, compared to controls. Polysomnographic abnormalities were not different in patients reporting good or poor sleep and were not correlated to clinical and demographic variables. The PLMS index was significantly higher in patients with ALS than in healthy subjects, and 22 patients (53.6%) showed a PLMS index > 15/h, vs 4 (15.4%) controls (P < 0.001). Finally, two patients with ALS (4.9%) had RBD, and two more patients presented RSWA (4.9%), whereas no controls showed abnormalities of REM sleep. Conclusion Patients with ALS frequently present abnormalities of sleep that can be documented both at the clinical interview and at the polysomnographic evaluation, including insomnia, fragmented sleep, and increased PLMS. Moreover, abnormalities of REM sleep can be found in some of these patients.

Background and objectives Several variables have been linked to a shorter survival in patients with amyotrophic lateral sclerosis (ALS), for example, female sex, older age, site of disease onset, rapid disease progression, and a relatively short diagnostic delay. With regard to marital status, previous studies suggested that living with a partner might be associated to a longer survival and a higher likelihood to proceed to tracheostomy. Therefore, to further strengthen this hypothesis, we investigated the role of marital status as a prognostic variable in a cohort of ALS patients. Methods We performed a retrospective analysis on 501 consecutive ALS patients for which a complete disease's natural history and clinical/demographic data were available. At diagnosis, 409 patients (81.6%) were married or lived with a stable partner, whereas 92 patients (18.4%) were single/widowed/divorced. Results In our ALS cohort, being married was associated with a median longer survival (married, 35 months [24-50] vs unmarried, 27 months [18-42]; P

Objective To explore the effectiveness of communication and the variables affecting the eye-tracking computer system (ETCS) utilization in patients with late-stage amyotrophic lateral sclerosis (ALS). Methods We performed a telephone survey on 30 patients with advanced non-demented ALS that were provisioned an ECTS device. Median age at interview was 55 years (IQR = 48–62), with a relatively high education (13 years, IQR = 8–13). A one-off interview was made and answers were later provided with the help of the caregiver. The interview included items about demographic and clinical variables affecting the daily ETCS utilization. Results The median time of ETCS device possession was 15 months (IQR = 9–20). The actual daily utilization was 300 min (IQR = 100–720), mainly for the communication with relatives/caregiver, internet surfing, e-mailing, and social networking. 23.3% of patients with ALS (n = 7) had a low daily ETCS utilization; most reported causes were eye-gaze tiredness and oculomotor dysfunction. Conclusions Eye-tracking computer system is a valuable device for AAC in patients with ALS, and it can be operated with a good performance. The development of oculomotor impairment may limit its functional use.

Background and purpose: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Although sleep disturbances are a candidate factor that may interfere with fatigue in patients with ALS, the role of sleep-related abnormalities in determining fatigue in ALS is unknown. Objective: To evaluate the frequency and determinants of fatigue in a group of 91 consecutive patients with ALS, with special attention to the relationship between fatigue and sleep problems. Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating ScaleRevised (ALSFRS-R), and Beck Depression Inventory (BDI). Results: The mean FSS score was 4.35 ± 1.1, and 48 patients with ALS (52.75%) reported clinical significant fatigue. FSS score correlated with ALSFRS-R score, forced vital capacity, ESS, BDI, and global PSQI score. Patients with fatigue were significantly more disabled and more frequently reported difficulties staying asleep and nocturnal complaints, such as nocturia and disturbing muscle cramps. After multivariate analysis, patients disability and nocturnal complaints were significantly associated with fatigue. Conclusion: In this study, we demonstrated that fatigue, a troublesome and disabling symptom in ALS, is associated with physical impairment and night-time complaints (such as nocturia and muscle cramps), suggesting that treating sleep problems might be useful in alleviating fatigue in these patients.

Objectives - To determine the causes and place of death in a cohort of Italian patients with amyotrophic lateral sclerosis (ALS). A better understanding of the likely causes of death in ALS might improve the palliative care at the end-of-life, whereas knowing the place of death will help to verify the need for highly specialized care services, e.g. hospice and nursing home. Patients and methods - Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M/F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Medical data for each individual patient were recorded in a large database throughout the disease course. Information concerning causes and place of death were obtained by consultation with relatives or the family physician. Results - Respiratory failure (terminal respiratory insufficiency, pneumonia) was the most frequent cause of death (81.3%), which included six cases (3.3%) who requested a terminal sedation. Sudden death and death during sleep accounted for by 6.0% and 6.6% of all deaths, respectively. Heart-related causes of death were relatively infrequent in our cohort, accounting for by 7.1 % of all deaths (i.e. sudden death: 6.0% and myocardial infarct: 1.1%). Patients (85.2%) died at home. Conclusions - The leading cause of death in ALS remains the respiratory failure, followed by the sudden death and death during sleep. Most patients in our cohort died at home, a choice that might be only partially driven by cultural factors. These findings might have a great impact on the development of the advanced and end-of-life palliative care and in the planning of specialized care services, as hospice and nursing home.

Background: High cerebrospinal fluid (CSF) and plasma levels of homocysteine (HC) have been reported in certain neurodegenerative disorders, such as Alzheimer’s, Parkinson’s diseases and, recently, amyotrophic lateral sclerosis (ALS). Objectives: To assay the CSF and plasma levels of HC in ALS patients and controls, and to evaluate the relationship between HC levels and clinical variables of the disease. Methods: Cerebrospinal fluid from sixty-nine (M/F 1.87) and plasma from sixty-five ALS patients (M/F 1.83) were taken and stored at −80°C until use. Controls (CSF = 55; plasma = 67) were patients admitted to our hospital for neurological disorders with no known relationship to HC changes. CSF and plasma from ALS patients and controls were obtained as a necessary step of the diagnostic workup. HC levels in CSF and plasma were assayed using a high performance liquid chromatograph (HPLC) and a fluorimeter detector. Results: The median level of total HC in the CSF of ALS patients was 0.46 μM, significantly higher than that of the controls (0.24 μM, +91.6%, P

Background and purpose Vesicle-associated membrane-protein-associated protein B (VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER function, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminal domain, named MSP, is cleaved and secreted, serving as an extracellular ligand. VAPB mutations are linked to autosomal-dominant motor neuron diseases, including amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is also suspected in sporadic ALS (SALS). Methods The expression pattern of VAPB cleavage and secreted products in the peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patients and neurological controls was assessed. PBL from healthy controls were also analyzed. Assays were carried out through western blotting, using an anti-VAPB (N-terminal) antibody. Results Two VAPB fragments containing the MSP domain (17 kDa and 14 kDa molecular sizes) were identified in PBL of SALS and controls, with no significant differences amongst groups. In CSF, only the 14 kDa VAPB MSP fragment was expressed and a corresponding VAPA fragment was not detected. The CSF VAPB fragment was absent in 58.7% of SALS patients, of whom 79.2% were bulbar onset (P = 0.001, bulbar versus spinal). Conclusions The absence of the CSF VAPB MSP fragment from most bulbar-onset SALS patients suggests a specific alteration of brain-derived VAPB cleavage and secretion in this group of patients, and hints at a role of VAPB in the pathophysiology of this motor neuron disease.

Dysembryoplastic neuroepithelial tumor (DNT) is a clinically benign stable lesion, most frequently located in the temporal and frontal lobes, often responsible for epilepsy in young adults. We describe an unusual case of DNT in the brainstem of a 45-year-old woman. Brain MRI showed a multicystic-like lesion localized in the left inferior pons, involving the ipsilateral cerebellar peduncle and partially dislocating the fourth ventricle. The specific pattern of MRI and CT appearance of DNT and its benign course (our patient is clinically stable with unchanged MRI images at two year follow-up) may help differentiate this tumor from other lesions, i.e. ganglioglio-mas and glioneural malformations.

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.

A 37-year-old office worker was referred to our hospital with severe weakness, malaise, headache and altered mental status. He was mildly febrile (37.5°C) with reported episodes of agitation. A blood count revealed 709 720 white blood cells (WBC) / μl with 33 000 platelets/μl. The clinical, imaging and laboratory workup led to a diagnosis of acute lymphoblastic leukaemia (ALL) …

It has been suggested that β-N-oxalylamino- l -alanine, a non-protein amino acid present in the Lathyrus Sativus seeds, may play a role in the etiopathogenesis of neurolathyrism, a toxic form of motor neuron disease clinically characterized by a severe spastic paraparesis. In order to investigate the mechanisms of β-N-oxalylamino- l -alanine-mediated cell death, we studied the effect of this neurotoxin as well as other excitatory amino acids agonists on the growth and survival of motoneuron hybrid ventral spinal cord 4.1 cells. β-N-oxalylamino- l -alanine was toxic to ventral spinal cord 4.1 cells in a concentration-dependent fashion (0.5–10 mM). Among the excitatory amino acids tested, only glutamate (1–10 mM), quisqualate (1 mM) and, with less extent, β-N-methylamino- l -alanine (10 mM) induced a significant reduction of cell survival. The effect of Lathyrus Sativus neurotoxin was a slow process, becoming apparent only after 24–48 h of incubation. Interestingly, a mathematical analysis applied to the time course and dose curve of β-N-oxalylamino- l -alanine toxicity suggested that even for very low concentrations of the amino acid it is theoretically possible to predict a time-dependent effect. The cell death was not blocked by antagonists of N-methyl- d -aspartate or non-N-methyl- d -aspartate receptors; aurintricarboxylic acid and α-tocopherol gave a partial protection; cysteine (1 mM) prevented the toxic effect of both Lathyrus Sativus neurotoxin and glutamate as well as quisqualate. Morphologically, in the presence of either β-N-oxalylamino- l -alanine, glutamate or quisqualate, ventral spinal cord 4.1 cells showed apoptotic features also confirmed by ISEL technique and agarose gel electrophoresis of genomic DNA. Thus, our results suggest that in ventral spinal cord 4.1 motoneuron hybrid cells, in the absence of functional synaptic excitatory amino acid receptors, β-N-oxalylamino- l -alanine induces cell degeneration through an apoptotic mechanism, possibly mediated by a block of cystine/glutamate X−c antiporter.

Objective: Recent evidence suggests that intermediate-length polyglutamine (PolyQ) expansions in the ataxin-2 ( ATXN-2 ) gene are a risk factor for amyotrophic lateral sclerosis (ALS). This work was undertaken with the aim to investigate the frequency of ataxin-1 ( ATXN-1 ) and ATXN-2 PolyQ expansions in a cohort of patients with sporadic ALS (sALS) and patients with familial ALS (fALS) from southern Italy. Methods: We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders. Results: We found significantly higher intermediate PolyQ expansions ≥32 for ATXN-1 alleles and ≥28 for ATXN-2 alleles in the sALS cohort ( ATXN-1 : ALS, 7.07% vs controls, 2.38%; p = 0.0001; ATXN-2 : ALS, 2.72% vs controls, 0.5%; p = 0.001). ATXN-1 CAT and ATXN-2 CAA interruptions were detected in patients with ALS only. Age at onset, site of onset, and sex were not significantly related to the ATXN-1 or ATXN-2 PolyQ repeat length expansions. Conclusions: Both ATXN-1 and ATXN-2 PolyQ intermediate expansions are independently associated with an increased risk for ALS.

Ninety-two patients affected by chronic cerebrovasculopathy were treated with cytidine diphosphate choline (CDP-choline) 1000 mg/day i.m. or with placebo, in a double-blind study. Two cycles of therapy of 4 weeks each were performed, with an interval of 1 week. There were 46 patients in each group with chronic cerebrovascular diseases, and the two groups were comparable as far as mental deterioration was concerned. The following psychometric tests were administered: Toulouse-Pieron (attention to non-verbal stimuli), Randt Memory test (memory), Sandoz Clinical Assessment of Geriatrics (SCAG, measurement of the behavioral and emotional control). The comparison between the two groups revealed significant improvements in the CDP-choline group compared with the placebo group in some of the attention capabilities (decrease in the number of wrong answers at the Toulouse-Pieron test), of the mnemonic capabilities (‘General Information’ subtest of Randt Memory test) and behavioral capabilities (SCAG ‘affective disturbances’ score). No side-effects were detected in the CDP-choline group.

We report on a patient with bulbar-onset, clinically defined, sporadic amyotrophic lateral sclerosis (ALS) who also showed a Chiari I malformation. This malformation, otherwise asymptomatic, was detected during the diagnostic work-up for ALS. To our knowledge this is the first report of an association between these two relatively uncommon disorders. Since our patient worked for many years as a bus-driver and because the ALS symptoms began in the brainstem region, we suggest that his hindbrain anomaly, along with the mechanical stress on the spine and cranio-vertebral junction due to the daily driving, might have played a role in the region-specific onset of ALS. Language: en

TAR-DNA-binding protein 43 (TDP-43) has recently been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS) and SOD1 negative familial cases with amyotrophic lateral sclerosis (FALS). TDP-43 is evolutionarily conserved, consisting of two RNA recognition motifs and a glycine-rich C-terminal domain. It is involved in the regulation of expression and splicing, and in other cellular processes such as microRNA biogenesis, apoptosis and cell division.1 2 Starting in early 2008, dominant mutations in TARDBP gene have been reported by several groups as a primary cause of ALS. To date, a total of 30 mutations of TARDBP have been reported not only in SOD1 -negative FALS cases (∼3%) but also in SALS cases (∼1.5%). All but one of the mutations identified (D169G) reside in exon 6 of the TARDBP gene, which encodes for the C-terminal glycine-rich domain of TDP-43. All of these mutations are dominantly inherited missense changes with the exception of a truncating mutation (Y374X) at the extreme C terminus of the protein.3 In this study, in order to investigate the presence and frequency of TARDBP mutations in a cohort of 310 south Italian patients affected by ALS, we performed a mutational screening of the exon 4 and exon 6 of the gene in SOD1 -negative FALS and SALS patients. …

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive motor neuron cell death. Etiopathogenesis is still imperfectly known and much effort have been undertaken to find a biological marker that could help in the early diagnosis and in the monitoring of disease progression. Cerebrospinal fluid (CSF) concentrations of tau, an axonal microtubule-associated protein, have been measured in ALS with levels found increased in some studies and unchanged in others. Methods: Total CSF tau level was assayed in a population of ALS patients (n = 57) and controls (n = 110) using a specific ELISA method. Results: No significant differences in the median CSF tau levels between ALS cases and controls were found [ALS: 126 pg/ml (78–222); controls: 112 pg/ml (71–188), P = ns]. In the ALS group, the bulbar-onset patients showed increased CSF tau levels as compared with the spinal-onset cases. These differences might be related to the higher age of the bulbar-onset patients. Further, no correlations were found between CSF tau concentrations and the rate of progression of the disease. Conclusions: These results do not support the hypothesis that total CSF tau protein is a reliable biological marker for ALS.

[3H]Flunitrazepam (FNZ) binding to cortical neurons from fetal rat brain was investigated in vitro. The use of a synthetic medium specific for neurons made it possible to plot a developmental curve of3H-FNZ binding in an almost pure neuronal culture. Detectable specific binding was present in vitro at time 0 (that is, the 16th gestational day). A progressive increase of binding, due to an increment in the number of recognition sites, was observed on the subsequent days. The affinity of the specific binding sites to3H-FNZ was enhanced by the addition of exogenous GABA, whereas the density was not affected. © 1990 Plenum Publishing Corporation.

The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.

We present a 72-year-old woman with progressive dysphagia, dysarthria and tongue palsy who was initially diagnosed with bulbar-onset amyotrophic lateral sclerosis (ALS). However, the absence of atrophy or fasciculations in the tongue, as in other voluntary muscles, and the lack of reproducible neurophysiological evidence of denervation, prompted a revision of the diagnostic work-up, which eventually led to the discovery of a carcinoma of the tongue. This case report describes a relatively rare type of oropharyngeal carcinoma that, in its early stage, resembled a bulbar-onset ALS. This differential diagnosis is unusual, and it was fostered by the persistent lack of atrophy of the tongue and the absence of spreading of signs and symptoms of motor neuron degeneration.

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Objective: To identify factors associated with tolerance and survival after noninvasive positive-pressure ventilation (NIPPV) and to investigate the influence of NIPPV on lung function in patients with ALS. Methods: NIPPV was offered to 71 patients with ALS in accordance with currently published guidelines. Effects of NIPPV on lung function and factors influencing tolerance and survival after NIPPV were studied. Results: Forty-four patients (61.9%; 95% CI: 50.6 to 73.2) tolerated NIPPV (NIPPV use >= 4 h/day) and 27 (38.1%; 95% CI: 26.8 to 49.4) were intolerant (NIPPV use < 4 h/day). Patients with mild or moderate bulbar symptoms were more likely to tolerate NIPPV than those with severe impairment (odds ratio = 6.09, 95% CI: 1.18 to 31.52, p = 0.031). After NIPPV introduction, a slower decline in forced vital capacity (FVC) was observed in tolerant vs intolerant patients (p = 0.002). The slope of FVC decline after NIPPV initiation (risk ratio [RR]: 0.78, 95% CI: 0.65 to 0.94, p = 0.01) together with NIPPV tolerance (RR: 0.32, 95% CI: 0.13 to 0.78, p = 0.013) were the only independent predictors of survival in the overall group of patients. In multivariate analysis, body mass index was the most powerful predictor of longer survival after NIPPV in tolerant patients (RR: 0.77, 95% CI: 0.61 to 0.96, p = 0.022). Conclusion: Survival after noninvasive ventilation was independently related to ventilatory use (>= 4 h/day) and to the modifications of forced vital capacity decline after treatment initiation. The severity of bulbar impairment and the nutritional status of the ALS patients at the introduction of ventilation may predict tolerance and survival.

To reconcile the autoimmune and excitotoxic hypotheses regarding the etiology of amyotrophic lateral sclerosis (ALS), we injected rats intraperitoneally with ALS immunoglobulins and monitored CSF glutamate, aspartate, glutamine, and glutathione. CSF glutamate was significantly increased at 24 and 72 hours compared with both basal levels and disease control injected rats. CSF aspartate was increased at 72 hours. Glutamine and glutathione were unchanged. These data suggest that ALS immunoglobulins may enhance CSF glutamate and aspartate levels and contribute to motoneuron injury.

The aim of our study was to analyze the dropout rate in patients with relapsing-remitting multiple sclerosis (RRMS) under long-term treatment with the three commercially available interferon beta (IFNbeta) preparations. According to the drug taken, we divided 122 RRMS patients into 4 groups: Betaferon group, 56 patients taking INFbeta-1b (24 MIU weekly, subcutaneous injections); Avonex group, 38 patients taking IFNbeta-1a (6 MIU weekly, intramuscularly); Rebif group, 18 patients taking INFbeta-1b (18 MIU subcutaneously). Ten patients who shifted from Betaferon to Avonex were included in a fourth group. Dropouts were registered every trimester with the related cause. Data were evaluated using Kaplan-Meier survival analysis and log-rank test. During the observation period of five years, 48 patients (39.9%) dropped out: 48% of the patients in Betaferon group withdrew at a median of 758 days, 26% of the Avonex group at 356 days; 38% of the Rebif group at 421 days, and 40% of those who shifted from Betaferon to Avonex at 259 days. The differences between groups were not significant on survival analysis. Patients receiving higher dose treatment (Betaferon and Rebif groups) dropped out mainly for clinical adverse events; conversely, patients receiving lower dose therapy (Avonex group) dropped out most often for inefficacy. Patients who shifted to a lower dose treatment (fourth group) had a dropout rate similar to that of the initial treatment. Our data showed that one-third of the patients stopped the therapy, mostly for adverse events and then for inefficacy, while the remaining two-thirds were still on treatment without problems up to 5 years of follow-up. Compliance seems related to the dose of the drug, but further analysis is needed to confirm our data.

We report on a patient with bulbar-onset, clinically defined, sporadic amyotrophic lateral sclerosis (ALS) who also showed a Chiari I malformation. This malformation, otherwise asymptomatic, was detected during the diagnostic work-up for ALS. To our knowledge this is the first report of an association between these two relatively uncommon disorders. Since our patient worked for many years as a bus-driver and because the ALS symptoms began in the brainstem region, we suggest that his hindbrain anomaly, along with the mechanical stress on the spine and cranio-vertebral junction due to the daily driving, might have played a role in the region-specific onset of ALS.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive degeneration of motoneurons in spinal cord and brainstem. The telomeric copy of a duplicated gene termed survival motor neuron (smn), which maps to chromosome 5q13, has been found to be deleted in most patients. The encoded gene product is a novel protein which recently has been shown to accumulate in specific nuclear organelles (gemini of coiled bodies, GEMS), and to play a part in the formation of the spliceosome complex. We have cloned and sequenced the rat smn cDNA. Antibodies generated against an N-terminus peptide recognized a main protein of 32 kDa in immunoblots of rat embryonic tissue extracts. Minor bands of 35 kDa, 45 kDa and, in perinatal muscle, of 24 kDa were also specifically detected, indicating that SMN is expressed as different molecular forms. Subcellular fractionation indicated that the 32 kDa form is mainly soluble, while the 35 kDa and 45 kDa products segregate to the microsomal-mitochondrial fraction. SMN protein is highly regulated during development: expression is high in embryonic tissues (central nervous system, muscle, lung and liver), and then progressively decreases to very low levels in most tissues of the adult. The demonstration of different molecular forms of SMN along with its developmental regulation may help to understand the contribution of this protein in the appearance of SMA phenotype.

Calbindin D28K (CB), a cytosolic calcium binding protein (CBP), forms a macromolecular complex with the polypeptide mellitin (ME) the absence of calcium, which can be reversibly dissociated by the addition of Ca2+. The molar ratio of CB:ME constituted in this complex is 1:4, suggesting that CB interacts with the tetrameric form of ME. Like free tetrameric ME, the CB:ME complex does not migrate into 15% non-denaturing polyacrylamide electrophoretic gels, although both constituents migrate normally after irreversible complex denaturation by heating in sodium dodecyl sulphate (SDS). The interaction of these two proteins can be distinguished from the association of calmodulin (CM) with ME, which forms a reversibly dissociable, equimolar complex in the presence of Ca2+ and a stable non-migrating complex (molar ratio = 1:12) in its absence. Thus, CB and CM appear to bind ME under different Ca2+ regulatory control, suggesting possible roles for CB as a Ca(2+)-dependent regulatory binding protein.

Objective: To assess the frequency and the phenotype of a large series of Italian sALS and fALS with C9ORF72 repeat expansions. Background Recently we found that large expansions of hexanucleotide repeats (GGGGCC) in the first intron of the C9ORF72 gene, located in the chromosome 9p21, are related to familial and sporadic ALS cases(Renton et al, 2011). Design/Methods: We assessed 126 index fALS (106 Italians, 20 of Sardinians) and 601 sALS (485 Italians, 116 Sardinians), negative for other ALS-related genes mutations. Patients were collected through the ITALSGEN consortium. Repeat primer PCR to screen the presence of the hexanucleotide expansion in the first intron of C9ORF72 have been performed. Controls were 353 neurologically healthy subjects of Italian ancestry and 96 of Sardinian ancestry. Results: In controls, the number of repeats was under 25 (range 0-23). Among Italians 16 sALS (3.3%) and 42 (39.6%) had an increase of C9ORF72 gene repeats. Among Sardinian 9 sALS (7.8%) and 11 fALS (55.5%) had an increase of C9ORF72 gene repeats. In Italians, a north to south decreasing gradient of C9ORF72 hexanucleotide repeat expansions was found. Compared to patients without repeats, subjects with repeat expansion had a higher frequency of frontotemporal dementia (FTD)(p=0.0001). A tendency toward an anticipation of age at onset was found, with a greater anticipation if the transmitting parent was the mother. The penetrance was 63% (95% CI, 56-69%) at 70 years, and 81% at 80 years (75-87%). The penetrance was significantly higher in men (70% at 70 years) than in women (54% at 70 years)(p=0.03). Conclusions: Th expansions of the C9ORF72 gene are the most common genetic mutation in Italian sALS and fALS and are particularly frequent in subjects of Sardinian ancestry. The complexity of the phenotype of pedigrees related to this mutation, which include cases with ALS, ALS-FTD and FTD, challenge the current notion of familial ALS. Disclosure: Dr. Chio has nothing to disclose. Dr. Borghero has nothing to disclose. Dr. Sabatelli has nothing to disclose. Dr. Corbo has nothing to disclose. Dr. Mora has nothing to disclose. Dr. Giannini has nothing to disclose. Dr. Conforti has nothing to disclose. Dr. Penco has nothing to disclose. Dr. Calvo has nothing to disclose. Dr. Pugliatti has nothing to disclose. Dr. Sotgiu has nothing to disclose. Dr. Logroscino has received personal compensation for activities with Novartis, Glaxo and Boerhinger. Dr. Traynor has received personal compensation in an editorial capacity for the journal Neurology. Dr. Renton has nothing to disclose. Dr. Majounie has nothing to disclose. Dr. Lauria has nothing to disclose. Dr. Caponnetto has nothing to disclose. Dr. Mandrioli has nothing to disclose. Dr. Salvi has received research support from Fondazione Hilarescere. Dr. Volanti has nothing to disclose. Dr. La Bella has nothing to disclose. Dr. Monsurro has nothing to disclose. Dr. Zollino has nothing to disclose. Dr. Ossola has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Restagno has nothing to disclose.

In the last few years, an increasing amount of studies have been dedicated to the etiopathogenesis of age-related neurodegenerative disorders, such as Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. The discovery of synthetic, as well as natural molecules, able to reproduce in the animals biochemical and morphological alterations of neurodegenerative disorders, has provided a major impetus to the "environmental" hypothesis of neurodegeneration. In this review, following a brief description of the ability of the nervous system to counteract the degenerative process, the main neurotoxic-based animal models for neurodegeneration are examined. These might give us interesting clues for understanding the pathogenetic mechanism(s) of neurodegenerative process.

In Italy, the oldest country in the world (1), over 60 years is 24,5%, where the elderly people, with chronic pathologies needs of healthcare in different ways of Telemedicine (2), and the emergency for Elderly alone need new professional roles of healthcare at home, as “social healthcare keeper”(3), and many applications of Tele-healthcare and Tele-diagnosis (4). We introduce an Ultrasound System (USy): a modular integrated system diagnosis in a PC for images diagnosis, acquisition and transmission signals within the healthcare assistance (Fig.1); 128 channels of digital real-time, high resolution ultrasound imaging; probes and software are from Terason Inc. (USA), while ECG, Spirometry and PulseOxymetry are from QRS Diagnostic Inc (USA). It is a general purpose echo-graphic on outside the PC in Windows; the size is like the mobile phone; the sensor system is complete: linear plane, convex, endo-cavity, phased array. The most innovative feature is the micro miniaturized chip (Fig.2): high weight, costs and power waste reduction. The multifunction integration on a PC platform is under construction by Prisma Imaging Western Europe (Italy) and the modules in diagnosis can be integrated in desktop and laptop, in palm also for EDP (Fig.3). The software is compatible Microsoft Win2000 or XP OS and consequently it is easy to use, also it includes a dedicated Electronic Patient Folder. Connecting Medical Informatics and Bio-Informatics R. Engelbrecht et al. (Eds.) ENMI, 2005 1210