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Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A, 3 in both CLCN1 and SCN4A, 1 in ATP2A1, 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1, p.K1302R in SCN4A, p.L208P in ATP2A1 and c.280–1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis.

Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE, implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, an sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10 mg/kg/day sc; sGC-treated) until G20. Fetal weight was reduced ( P = 0.004) at G20 in RUPP but not in sGC-treated RUPP compared with Sham, the control group. At G20, uterine artery resistance index (UARI) was increased ( P = 0.010) in RUPP, indicating poor placental perfusion; proportional junctional zone surface area was elevated ( P = 0.035), indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid-binding protein (hFABP) was increased ( P = 0.008) in RUPP but not in sGC-treated RUPP, suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI ( P < 0.001), proportional junctional zone surface area ( P = 0.013), and placental hFABP protein expression ( P = 0.008) were increased in sGC-treated Sham, suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

About 20% of patients with myasthenia gravis (MG) may develop myasthenic crisis (MC) requiring ventilation, either invasive (MV) or non-invasive (NIV) and intensive unit care (ICU). NIV failure in patients with MC can occur up to 60% of cases admitted to ICU. Moreover it is not known the outcome of MC receiving NIV. Purpose of this study was to identify predictors of outcome in MC who underwent non-invasive ventilator support outside ICU setting. We enrolled 90 patients, 53 females and 37 males admitted to University Hospital of Modena (Italy) between January 2000 and September 2020. Median age at MC was 65 years. Thirty-four patients (37.8%) required MV. Thymectomy was performed in 45 cases, associated with thymoma in 55%, with hyperplastic thymus in 33%. First-line treatment was plasmaexchange (38.8%) or intravenous immunoglobulins (45.6%). Males exhibited higher risk of MV than females .Patients in MV were treated with plasmaexchange as first-line therapy . Our in-hospital mortality rate was low. Nine patients underwent tracheostomy which was significantly related to male gender. Comorbidities had significant effect on length of ICU .Our study confirms as predictors of prognosis in our patients male gender, older age at onset, infections as trigger, pneumonia.

ObjectiveTo define the current treatment practice of Guillain-Barré syndrome (GBS).MethodsThe study was based on prospective observational data from the first 1,300 patients included in the International GBS Outcome Study. We described the treatment practice of GBS in general, and for (1) severe forms (unable to walk independently), (2) no recovery after initial treatment, (3) treatment-related fluctuations, (4) mild forms (able to walk independently), and (5) variant forms including Miller Fisher syndrome, taking patient characteristics and hospital type into account.ResultsWe excluded 88 (7%) patients because of missing data, protocol violation, or alternative diagnosis. Patients from Bangladesh (n = 189, 15%) were described separately because 83% were not treated. IV immunoglobulin (IVIg), plasma exchange (PE), or other immunotherapy was provided in 941 (92%) of the remaining 1,023 patients, including patients with severe GBS (724/743, 97%), mild GBS (126/168, 75%), Miller Fisher syndrome (53/70, 76%), and other variants (33/40, 83%). Of 235 (32%) patients who did not improve after their initial treatment, 82 (35%) received a second immune modulatory treatment. A treatment-related fluctuation was observed in 53 (5%) of 1,023 patients, of whom 36 (68%) were re-treated with IVIg or PE.ConclusionsIn current practice, patients with mild and variant forms of GBS, or with treatment-related fluctuations and treatment failures, are frequently treated, even in absence of trial data to support this choice. The variability in treatment practice can be explained in part by the lack of evidence and guidelines for effective treatment in these situations.

We studied 33 patients affected by juvenile and adult myotonic dystrophy type 1 (DM1). The aim of the study was to assess clinical and laboratory parameters that could predict the requirement of noninvasive ventilation (NIV) in DM1. Secondary outcome was to assess the interplay between genetic profile, muscle impairment severity and presence of cardiac comorbidities.Patients with genetic diagnosis of DM1 were recruited. An abnormal trinucleotide repeat (CTG) expansion of dystrophy protein kinase gene (DMPK) on chromosome 19q13.3 was the prerequisite for inclusion. The number of triplet repeats was measured in genomic DNA to classify subjects. A multidisciplinary team evaluated the patients every 6-8 months up to 18 years with serial cardiological and respiratory function assessments. Neurological progression was monitored using a validated DM1-specific rating scale (MIRS). Independent variables considered for the study outcomes were gender, genetic status, age of presentation, MIRS scores, and results of pulmonary function tests (PFTs).Patients were 17 males (51.5%) and 16 females (48.5%). 16 cases were younger than mean age of 31.4 years, the remaining 17 were up to 65. 12 subjects (36.4%) underwent NIV during follow up. Cardiac comorbidities were detected in 63.6% of cases and in 91% of patients in NIV. Among PFTs, forced vital capacity (FVC) was a reliable indicator of respiratory decline. FVC values were significantly associated with clinical muscle severity assessed by MIRS.Severity of muscular impairment, CTG expansion size, age and presence of cardiac comorbidities predict respiratory impairment in DM1.

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50-60% of patients may progress within 1-2 years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24 months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50 years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.

We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults. (C) 2017 Elsevier B.V. All rights reserved.

Bimetallic nanoparticles (BNPs) have shown better biological potential compared to their monometallic counterparts owing to the synergistic effect produced by these alloys. In this study, selenium-capped silver nanoparticles (Ag@Se NPs) were synthesized using an Ocimum tenuiflorum extract. These BNPs were characterized using UV-visible, Fourier transform infrared spectroscopy, nanoparticle tracking analysis, electron microscopy and energy dispersive x-ray analysis. Response surface methodology was used to understand how extract volume and temperature influenced the zeta potential, hydrodynamic size and NP concentration. The phytoconstituents were identified using gas chromatography-mass spectrometry (GC-MS) and molecular docking studies were performed on B-DNA to determine possible genotoxicity. Antioxidant activities, in vitro cytotoxicity (3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay), and genotoxicity (Allium cepa root cells) of these BNPs, were also evaluated. A surface plasmon resonance band around 420 nm confirmed BNP formation with significant quantities of silver and selenium. The Ag@Se NPs displayed good stability, dispersity, antioxidant activity, and compatibility at low concentrations but showed significant cytotoxicity and genotoxicity at high concentrations. Molecular docking analysis showed weak interactions between the plant constituents and B-DNA, suggesting no genotoxicity. These results provide an insight into the conditions required for optimal production of eco-friendly Ag@Se NPs with interesting biological properties.

50%-60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables.We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients.Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL.Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening.

Aerobiology is an interdisciplinary science where researchers with different backgrounds are involved in different topics related to microorganism, airborne biological particles, e.g. pollen and spores, and phenology. Some concepts, words or expressions used in aerobiology have a clear definition, but are however frequently misused. Therefore, the working group “Quality Control” of the European Aerobiology Society (EAS) and the International Association of Aerobiology (IAA) would like to clarify some of them, their use and presentation.

Incidence of neuroepithelial Primary Brain Tumors (nPBT) varies, ranging from 7.3 to 11.6 cases/100,000/year across Europe. We present incidence and survival of nPBT in the Emilia-Romagna region (ER), Italy. This study is the largest in Southern Europe. Specialists in neurosurgery, neurology, neuroradiology, oncology, radiotherapy, genetics, and pathology of ER notified all suspected nPBT adult cases residing in ER (4,337,966 inhabitants) observed during 2009. Furthermore, through ICD-9 discharge codes, we identified and reviewed all possible cases. Neuroepithelial PBT diagnosis was based on histological or radiological findings. We included 400 incident nPBT cases, of which 102 (25%) were retrospectively identified. These latter were significantly older. The standardized incidence was 10.5/100,000/year (95% CI 9.4–11.5), higher for men. It was 9.2/100,000/year (95% CI 8.3–10.2) for astrocytic tumors, 0.6/100,000/year (95% CI 0.4–0.9) for oligodendroglial tumors, and 7.1 (95% CI 6.3–8.0) for glioblastoma (GBM). Among GBM patients, median survival was 249 days if prospectively identified vs. 132 days when identified through ICD-9 codes (pÂ

Background: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients. Methods: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment. Results: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival. Conclusions: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor.

Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.

The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0–3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8–13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6–14.6), and 9.3 months (95 % CI 8.1–10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5–22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only.

We evaluate the factors predictive of prognosis in 91 Caucasian patients affected by ocular myasthenia gravis (OMG), followed at our Institution during an observational time, ranging from 12 to 240 months. The Myasthenia Gravis Foundation of America (MGFA) clinical classification was used to grade the disease severity. We considered as outcome measures the variation in two subscores, ocular (O-QMG) and nonocular (NO-QMG); the last one reflected bulbar, neck, extremity functions. None of the independent variables evaluated for association with the outcome, as age of onset, type of therapy, length of interval between first and last examinations, and presence of antibodies to acetylcholine receptors (AChR-Abs) significantly affected the evolution of O-QMG and of NO-QMG. Health-related quality of life (HRQol) was assessed in 63 patients. Variations of diplopia or ptosis did not affect significantly physical (PCS) or mental composite subscores (MCS) of the Short-Form Health Survey (SF-36). Human leukocyte antigen (HLA) genotyping was studied to explore whether HLA class I and II allelic distribution differed among MG patients and controls. None of the studied HLA alleles significantly differed between OMG patients and controls. Similarly, none of the alleles with frequencies higher than 15% either in OMG patients or in controls was significantly associated, after Bonferroni correction, with the presence or absence of anti-AChR-Abs in serum.

Background As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Methods Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Results Two hundred sixty-seven GBM patients (median age, 64 y; range, 29–84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2–12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0–18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248–0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388–0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328–0.986; P = .0446). Conclusions The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.

Neuropathy associated with IgM monoclonal gammopathy (MGUS) represents distinctive clinical syndrome, characterized by male predominance, late age of onset, slow progression, predominantly sensory symptoms, deep sensory loss, ataxia, minor motor impairment. More than 50% of patients with neuropathy-associated MGUS possess antibodies against myelin-associated glycoprotein (MAG). Purpose of our study was to assess effects on disease progression of demographic, clinical and neurophysiological variables in our large cohort of patients.Forty-three Caucasians patients were followed every eight months for median duration time of 93 months. Extremity strength was assessed with Medical Research Council (MRC) Scale, disability with overall disability status scale (ODSS), modified Rankin Scale and sensory function with Inflammatory Neuropathy Cause and Treatment (INCAT) sensory scale (ISS). Statistical analyses were conducted with parametric or non-parametric measures as appropriate. Survival analysis was used to test predictive value of clinical, demographical and neurophysiological variables. Variance analysis was conducted to explain difference on MRC between patients and groups at different time from onset.Results showed that demyelinating pattern, older age and absence of treatment were significant risk factors for disability worsening. No other factors emerged as predictors including gender, ataxia and tremor at baseline, level of anti-MAG and IgM protein concentration in serum. Despite worsening of all outcome measures between first and last visit, quality of life (HRQol) judged by patients did not vary significantly.Our study provides evidence that electrophysiologic pattern, age of onset and absence of treatment are strong predictor of prognosis in anti-MAG polyneuropathy.

Hashimoto's encephalopathy is an often misdiagnosed, life threatening, condition which improves promptly with steroid therapy. Since clinical manifestations are heterogeneous and non-specific, the diagnosis is often difficult. Several case reports of Hashimoto's encephalopathy presenting with partial or generalised seizures are described, but only a few have focused on status epilepticus as the first clinical manifestation. We report two patients presenting with repetitive and prolonged seizures characterised by progressive reduction in contact and reactivity associated with frontal/diffuse polyspike-and-wave activities. This condition, which can be interpreted as a form of non-convulsive status epilepticus (NCSE) of frontal origin, was refractory to antiepileptic drugs but responded promptly to high doses of intravenous steroid treatment. In cases of unexplained encephalopathy with EEG documentation of NCSE, the early recognition and treatment of Hashimoto's encephalopathy may lead to a favourable prognosis. [Published with video sequences].

Polyneuropathies may exhibits clinical, electrophysiologic signs of neuromuscular junction impairment. Distal motor nerve terminals and neuromuscular junction contain pre or postsynaptically specific targets for circulating autoantibodies, if present in neuropathies. Motor nerve terminal blockade either reversible or permanent is a putative factor of muscle weakness. A 59-year-old patient exhibited oropharyngeal, facial, extremity weakness, fluctuating fatigability, and areflexia. Elecectrophysiologic studies showed purely motor axonal polyneuropathy. Thenar, facial slow rate repetitive stimulation revealed up to 47% decrement of compound muscle action potential size. Single fiber electromyography on voluntary activation confirmed increased jitter and impulse blocking in all muscles examined in one third of the fibers. Repeated testings for antibodies to gangliosides, acetylcholine, muscle tyrosine kinase receptors, voltage-gated calcium channels were negative. Oral pyridostigmine bromide improved bulbar symptoms. Pulse intravenous immunoglobulin, oral steroids, and azathioprine had steady benefit. Impairment of neuromuscular transmission if occurring in chronic axonal neuropathies highlights mechanisms and significance of neuromuscular chronic "synaptopathies."

Retinal migraine is a rare entity characterized by headache associated with transient monocular visual disturbances. While fully reversible monocular phenomena and normal ophthalmological examination between the attacks are the hallmark of retinal migraine according to International Headache Society (IHS) classification, 1 an association with persistent monocular visual loss and abnormal ophthalmological findings has been reported. 2 The pathogenesis of these persistent visual disturbances remains unclear, even if retinal spreading depression and vasospasm of retinal arterioles have been claimed. 2 We present the case of a patient who experienced persistent monocular visual loss after a retinal migraine attack and in whom alteration of the ipsilateral optic nerve was found at the magnetic resonance imaging (MRI) scan, suggesting an involvement of the optic nerve in retinal migraine. The patient described in this report is a 23-yearold woman with a history of headache, beginning in early adolescence with episodes of unilateral frontotemporal pulsating pain with side alternation, photophobia, and moderate intensity, often associated with transient unilateral monocular visual disturbances. These were characterized by a partial monocular visual filed defect (alternatively blurring, glittering, or blindness), often confined to a localized part of the unilateral visual field, lasting a few minutes and with side alternation of the affected eye among the headache attacks. The patient came to our emergency

To assess whether Parkinson Disease (PD) patients are impaired at perceiving emotions from facial and prosodic cues and whether any putative defective performance concerns recognition of a particular emotion.Braak et al. [1] demonstrated that in different stages PD pathology involves the nigrostriatal system, the amygdala, and the insular cortex. Discrete brain lesions to these structures can cause selective deficits in recognising facial and prosodic stimuli expressing particular emotions. However, the investigation of facial and prosodic emotional processing in PD patients has lead to conflicting results.We compared 27 cognitively unimpaired PD patients with control subjects by means of the Facial Emotion Recognition Battery and the Emotional Prosody Recognition Battery.PD patients were impaired in recognising, selecting, and matching facial affects. In particular, the Facial Emotion Recognition Battery demonstrated a severe impairment in recognising sad and fearful faces. In the Emotional Prosody Recognition Battery PD patients demonstrated a diffuse impairment, including the recognition of emotional and propositional prosody.Face emotion processing is impaired in PD patients, with a disproportionate deficit involving fear and sadness. The pattern of face expression processing impairment in PD patients might depend on the regional distribution of the pathology. The widespread involvement of both emotional and propositional prosodic processing parallels the aprosodic characteristics of Parkinsonian speech production.

Two novel cholesterol-based cytofectins containing primary amino head groups, glycylcholesteryl formylhydrazide (MS10) and beta-alanylcholesterylformylhydrazide (MS11), have been prepared and incorporated into unilamellar cationic liposomes in equimolar amounts with dioleoylphosphatidylethanolamine (DOPE) as colipid. Stable lipoplexes were formed with pGL3 DNA which afforded protection to the DNA from serum nuclease digestion. Packing of the DNA was shown by ethidium displacement to be more effective in MS11 lipoplexes. High transfection levels in three human transformed epithelial cell lines HeLa (cervical), SNO (esophageal), HepG2 (hepatocyte-derived), and the murine fibroblast line NIH-3T3 were achieved by both lipoplexes at liposome: DNA ratios of 6:1 and 7:1 ((w)/(w)) corresponding to +/- charge ratios of 1.6:1 and 1.9:1. MS11 lipoplexes, in particular, afforded high transfection activities in the presence of fetal bovine serum.

The application of homing peptides to direct DNA and RNA lipoplexes to target cells is a rapidly evolving area of study, which may find application in corrective gene therapy for the treatment of neoplasms and other disorders of a genetic origin. Here, a step-wise account of the assembly and characterization of hepatocellular carcinoma cell-specific DNA lipoplexes and their cytotoxicity assessment in and delivery to the human hepatocellular carcinoma cell line HepG2 is given.

Soybean rust (Phakopsora pachyrhizi) has recently invaded North America and has the potential to be the most destructive foliar disease of soybean. As part of the response to this threat, the Integrated Aerobiology Modeling System (IAMS) was constructed to forecast the aerial movement of this pathogen from subtropical to middle latitude portions of the continent. IAMS simulations have been conducted daily for the past two growing seasons and integrated with information from a nationwide observation network into a decision support system for soybean farmers. After the 2005 season, the United States Department of Agriculture reported that many millions of United States (U.S.) soybean hectares that would have been treated for soybean rust in 2005 were not due to this decision support system. In 2006, soybean rust appeared for the first time in the major U.S. soybean production region over 1000 km from known areas of inoculum production. IAMS predictions of the geographical extent and timing of disease symptom expression were well matched with subsequent observations of the disease in the field.

A wide range of axonal peripheral neuropathies, especially subacute sensory and motor neuronopathies have been reported as remote effect of cancer. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) most often occurs isolated but it may accompany several autoimmune diseases. The association of CIDP and carcinoma is rare and its relevance is still debated. Few cases have been associated with gastrointestinal cancers. This 53-year old man was admitted in December 1989 because of severe extremity weakness after EBV infection. Neurologic examination showed facial paresis, proximal and distal limb weakness, areflexia, distal loss for touch and deep sensibilities. Patient recovered with PE but mild symptoms and signs persisted in the limbs. In June 1997, patient developed acute relapse of his neuropathy after an episode of pneumonia. Electrophysiology, CSF and nerve biopsy were consistent with CIDP. Search for anti-nerve antibodies was negative except for anti-neurofilament IgM. IVIG had partial benefit. During the following four years, patient received IVIG 1 g/Kg monthly; however he continued to experience relapses of the neuropathy often occurring after trivial infections. Laboratory tests (monoclonal IgG; elevated SR and WB count, serum electrophoresis, carcinoembryonic antigen titer) suggested a systemic disease. In September 2001 a rectosigmoidal adenocarcinoma with bladder and liver metastases was discovered on abdominal CT scan and surgically treated. Patient's general and neurologic conditions rapidly deteriorated despite of chemotherapy with fluorouracil and leucovorin. He died on late summer 2002. We outline the unusual association of CIDP and intestinal cancer and the long interval elapsed between neuropathy onset and cancer detection.

Brachial amyotrophic diplegia (BAD) is defined the isolated upper limb weakness attributed to neurogenic atrophy, sparing lower extremity, respiratory and bulbar muscles. Although such phenotypes may be seen in number of conditions, previous reports pointed out that the label of BAD should refer to any patient with slowly and nonprogressive neurogenic atrophy of upper limbs remaining stable at least 18 months after initial presentation 50 year old man with unremarkable past history noticed after minor cervical spine trauma progressive weakness and wasting of left shoulder and arm which was followed within few months by gradual involvement of contralateral in relatively symmetric pattern. There were no symptoms in lower limbs, neck, bulbar muscles nor sphincter disturbances. On examination, patient exhibited a peculiar posture of both hands hanging loosely at his sides. There were fasciculations and atrophy of upper limb muscles. Reflexes could not be elicited in upper extremities but they were normal in the lower. Cranial nerves and sensory examination were unremarkable. Routine blood tests and search for GM1 antibodies were negative, whereas CK was found mildly elevated ( 361 mU/ml). Test for HIV-1 was positive with RNA level of 144.920 copies/ml and CD4 count 403/mm3. Electrophysiology showed in both sides low amplitude of compound muscle action potentials, mildly reduced velocity without evidence of conduction block or of temporal dispersion. Sensory conduction study was normal. On EMG, there was loss of motor units, acute and chronic neurogenic changes. Cervical MRI was normal. Patient neurological disability did not show progression. The case reported exhibits the following notable aspects: clinical and electrophysiological abnormalities fully restricted to upper limbs, lack of significant demyelinating features as well as of GM1 antibodies, absence of clinical signs related to immunosuppression due to HIV-1 infection.

Acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (AIDS-NHLs) consistently derive from B cells, are histologically heterogeneous, and are associated with distinct molecular pathways depending upon histology. Recently, it has been proposed that inactivating mutations of the bax death agonist may contribute to the pathogenesis of human tumors. In particular, among B-cell malignancies, BAX mutations have been detected at a certain frequency in Burkitt lymphomas. This study is aimed at defining the status of the BAX gene throughout the clinicopathologic spectrum of AIDS-NHL (n = 54), including AIDS-related Burkitt lymphoma (n = 14), AIDS-related Burkitt-like lymphoma (n = 8), AIDS-related diffuse large cell lymphoma (n = 15), AIDS-related primary central nervous system lymphoma (n = 6), and AIDS-related primary effusion lymphoma (n = 11). All 6 BAX exons and flanking sequences were subjected to mutational analysis by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing of positive cases. Mutations of BAX among AIDS-NHL were restricted to a cell line of AIDS-related primary effusion lymphoma, which harbored a frameshift mutation causing the introduction of a proximal stop codon. All other AIDS-NHL displayed wild-type BAX alleles. In order to investigate whether BAX inactivation in AIDS-NHL may occur through mechanisms other than gene mutation, bax protein expression was investigated by Western blot analysis or immunohistochemistry in selected cases. All AIDS-NHL analyzed expressed normal bax proteins. Overall, this study indicates that deregulation of apoptotic control in AIDS-NHL is not caused by BAX alterations. Genes Chromosomes Cancer 27:177-182, 2000.

AIDS-related non-Hodgkin lymphomas (AIDS-NHL) consistently derive from B-cells and are characterized by extreme clinical aggressiveness. At histological level, AIDS-NHL are classified as AIDS-related Burkitt's lymphoma (AIDS-BL), AIDS-related diffuse large cell lymphoma (AIDS-DLCL) and AIDS-related primary effusion lymphoma (AIDS-PEL). The role of cytokines in the pathogenesis and management of AIDS-NHL has been studied to a certain extent. Production of large quantities of human IL-10 occurs frequently in AIDS-BL and correlates with latent EBV infection of the tumor clone. Lesser amounts of the cytokine are released in EBV negative cases. The pathogenetic role of IL-10 in AIDS-BL is suggested by the observation that IL-10 antisense oligonucleotides inhibit proliferation of the lymphoma. A significant fraction of AIDS-BL cell lines produce TNFbeta. Among AIDS-NHL, the release of TNFbeta appears to be specific for AIDS-BL. The pathogenetic relevance of TNFbeta in lymphomagenesis is suggested by the observation that some BL cell lines use TNFbeta as an autocrine growth factor. Some cases of AIDS-BL, particularly those carrying EBV infection, also secrete IL-6, IL-7 and IL-12. With respect to AIDS-DLCL, many cases express the IL-6R, rendering these cells responsive to the paracrine stimulation by the IL-6 produced by nearby T-cells, macrophages and endothelial cells which are frequently abundant in these tumor samples. The tumor clone itself, however, generally fails to release IL-6. AIDS-PEL is characterized by secretion of large amounts of IL-6 and IL-10. Some PEL cases also release oncostatin M. Apart from human IL-6, PEL also express viral IL-6, which is encoded by the HHV-8 genome. The biological relevance of both IL-6 and IL-10 in PEL proliferation and growth has been recently clarified in vitro and in vivo. Overall, these data suggest that activation of different cytokine loops clusters with different clinico-pathologic categories of AIDS-NHL and may represent the potential target of novel therapeutic strategies.

Baruzzi A. (Chair), Albani F., Calbucci F., D’Alessandro R., Michelucci R. (IRCCS Institute of Neurological Sciences, Bologna, Italy), Brandes A. (Department of Medical Oncology, Bellaria-Maggiore Hospitals, Bologna, Italy), Eusebi V. (Department of Hematology and Oncological Sciences ‘‘L. & A. Seragnoli’’, Section of Anatomic Pathology at Bellaria Hospital, Bologna, Italy), Ceruti S., Fainardi E., Tamarozzi R. (Neuroradiology Unit, Department of Neurosciences and Rehabilitation, S. Anna Hospital, Ferrara, Italy), Emiliani E. (Istituto Oncologico Romagnolo, Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna, Italy), Cavallo M. (Division of Neurosurgery, Department of Neurosciences and Rehabilitation, S. Anna Hospital, Ferrara, Italy).

Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well-defined. In this work the expression of 19 microRNAs (miR-7, miR-9, miR-9∗, miR-10a, miR-10b, miR-17, miR-20a, miR-21, miR-26a, miR-27a, miR-31, miR-34a, miR-101, miR-137, miR-182, miR-221, miR-222, miR-330, miR-519d) was evaluated in sixty formalin-fixed and paraffin-embedded glioblastoma samples using a locked nucleic acid real-time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV-I). The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non-neoplastic references as controls, revealed a putative miRNA signature: mir-10b and miR-21 were up-regulated, while miR-7, miR-31, miR-101, miR-137, miR-222 and miR-330 were down-regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I-III, 3 miRNAs (miR-10b, mir-34a and miR-101) showed different regulation statuses between high-grade and low-grade tumors. miR-10b was up-regulated in high grade and significantly down-regulated in low-grade gliomas, suggesting that could be a candidate for a GBM target therapy. This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different-grade neoplasia could be characterized by different expression of specific miRNAs.

Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition.