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Geological survey and geochronological analyses were conducted in the Campo Imperatore plain to understand its Quaternary morpho-sedimentary and tectonic evolution. In the Late Pliocene-Early Pleistocene, low relief energy and steady and warm climatic conditions promoted a long phase of areal peneplanation, resulting in the formation of gently sloping landscape. With further regional uplift and changes in frequency/amplitude of the glacial-interglacial cycles (Early-Middle Pleistocene transition) and after establishment of the expansion-contraction cycles of the Apennine glaciers (Middle Pleistocene), the morpho-sedimentary processes become highly dynamic. In Middle Pleistocene, more than 100 meters of breccias deposited all along the slopes of the Gran Sasso range, followed by higher frequency processes of sedimentation, erosion and pedogenesis of Middle-Late Pleistocene to Holocene fluvio-glacial deposits. These have been progressively offset by synthetic and antithetic normal faults belonging to the Gran Sasso fault system, a 40-km-long seismogenic structure which released in the past earthquakes of Mw~7.

We present the first evidence of surface rupture along the causative fault of the 14 January 1703 earthquake (Mw 6.9, Italian central Apennines). This event was sourced by the ~30 km-long, Norcia fault system, responsible for another catastrophic event in Roman times, besides several destructive earthquakes in the last millennium. A dozen paleoseismological excavations have already investigated the surface ruptures occurred during the Holocene along the Cascia-Mt Alvagnano segments, as well as along secondary splays close to the Medieval Norcia Walls. Remarkably, the master fault bounding the Norcia-Campi basins have never be proved to rupture at the surface. An antique limekiln that was improvidently set across the main fault scarp provides the amazing evidence of an abrupt offset in the 1703 earthquake, which likely occurred during a liming process of carbonate stones. Obviously, the limekiln became useless, and was progressively buried by slope debris. The amount of the offset and the kinematics indicators surveyed in the site allow the strengthening of our knowledge on the seismogenic potential of the Norcia fault system, on its geomorphic rule, and on its impact on the human activities.

Intravenous immunoglobulin (IVIg) and corticosteroids are effective as initial treatment in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but little is known about the comparative risk–benefit profile of their long-term use in this disease. We compared the efficacy and tolerability of 6-month therapy with IVIg versus that with intravenous methylprednisolone. We did a multicentre, randomised, double-blind, placebo controlled, parallel-group study in patients with CIDP. We assessed efficacy and tolerability of IVIg (0·5 g/kg per day for 4 consecutive days) and intravenous methylprednisolone (0·5 g in 250 mL sodium chloride solution per day for 4 consecutive days) given every month for 6 months. Eligible patients had to be in an active or stationary phase of the disease. Allocation to treatment was centrally managed with a computer-generated, 1:1 randomisation scheme with a sequential block size of four. All patients and assessors were unaware of the treatment assignment. After therapy discontinuation, patients were followed up for 6 months to assess relapses. The primary outcome was the difference in the number of patients discontinuing either therapy owing to inefficacy or intolerance. Secondary endpoints included the difference in the proportion of patients experiencing adverse events or worsening after therapy discontinuation. This study is registered with EUDRACT, number 2005-001136-76. 45 patients (24 IVIg, 21 intravenous methylprednisolone) completed the study; one was excluded for inappropriate inclusion. More patients stopped methylprednisolone (11 [52%] of 21) than IVIg (three [13%] of 24; relative risk 0·54, 95% CI 0·34–0·87; p=0·0085). When adjusted for sex, age, disease duration, comorbidity, modified Rankin scale and ONLS scores at enrolment, and previous treatment with IVIg and steroids, the difference between the two groups remained significant (odds ratio 7·7, 95% CI 1·7–33·9; p=0·0070). Reasons for discontinuation were lack of efficacy (eight in the methylprednisolone group vs three in the IVIg group), adverse events (one in the methylprednisolone group), or voluntary withdrawal (two in the methylprednisolone group). Two patients on IVIg died during follow-up after the 6-month assessment. The proportion of patients with adverse events did not differ between the intravenous methylprednisolone group (14 [67%] of 21) and the IVIg group (11 [46%] of 24; p=0·1606). After therapy discontinuation, more patients on IVIg worsened and required further therapy (eight [38%] of 21) than did those on methylprednisolone (none of ten; p=0·0317). Treatment of CIDP with IVIg for 6 months was less frequently discontinued because of inefficacy, adverse events, or intolerance than was treatment with intravenous methylprednisolone. The longer-term effects of these treatments on the course of CIDP need to be addressed in future studies. Kedrion.

The only available treatment of traumatic spinal cord injury (TSCI) is high-dose methylprednisolone (MP) administered acutely after injury. However, as the efficacy of MP is controversial, we assessed the superiority of erythropoietin (EPO) versus MP in improving clinical outcome of acute TSCI. Patients aged 18 to 65 years after C5–T12 injury, and grade A or B of the ASIA Impairment Scale (AIS), admitted within 8 h, hemodynamically stable, were randomized to MP according to the NASCIS III protocol or EPO iv (500 UI/kg, repeated at 24 and 48 h). Patients were assessed by an investigator blind to treatment assignment at baseline and at day 3, 7, 14, 30, 60 and 90. Primary end point: number of responders (reduction of at least one AIS grade). Secondary end points: treatment safety and the effects of drugs on a number of disability measures. Frequentistic and post hoc Bayesian analyses were performed. Eight patients were randomized to MP and 11 to EPO. Three patients (27.3 %) on EPO and no patients on MP reached the primary end point ( p  = 0.17). No significant differences were found for the other disability measures. No adverse events or serious adverse events were reported in both groups. The Bayesian analysis detected a 91.8 % chance of achieving higher success rates on the primary end point with EPO in the intention-to-treat population with a 95 % chance the difference between EPO and MP falling in the range (−0.10, 0.51) and a median value of 0.2. The results of Bayesian analysis favored the experimental treatment.

Craniofacial pain syndromes are comprised of multiple pathological entities resulting in pain referred to the scalp, face, or deeper cranial structures. In a small subset of patients affected by those syndromes, pharmacological and physical therapies fail in alleviating pain. In some of those refractory patients surgical procedures aimed at relieving pain are indicated and have been adopted with variable results and safety profiles. In this review, the authors describe craniofacial pain syndromes that most commonly fail to respond to pharmacological therapies and may be amenable to tailored surgical procedures. In particular, trigeminal, glossopharyngeal, and occipital neuralgias are considered, as well as some primary headache syndromes such as cluster headache, short unilateral neuralgiform headache with conjunctival injection and tearing/short unilateral neuralgiform headache with autonomic symptoms, and migraine. Surgical techniques, including the implantation of deep brain or peripheral nerve electrodes with subsequent chronic stimulation, microvascular decompression of neurovascular conflicts, and percutaneous lesioning of neural structures are described. Finally, surgical indications, outcomes, and safety of these procedures are presented.

Background Increased titres of serum IgM antibodies to GM1 ganglioside are often associated with multifocal motor neuropathy (MMN). Testing for IgM antibodies to other antigens including GM2, the mixture of GM1 and galactocerebroside (GM1/GalC) and the disulfated heparin disaccharide NS6S were reported to increase the sensitivity of antibody testing in MMN even if it is unclear whether the specificity and positive (PPV) or negative predictive value (NPV) for MMN were also affected. Methods We measured IgM antibodies to GM1, GM2, galactocerebroside, GM1/GalC and NS6S in 40 consecutive patients with MMN and 142 controls with other neuropathies or related diseases and compared their sensitivity, specificity and PPV for MMN. Results With the only exception of anti-GM2 and, partially, anti-NS6S antibodies, IgM antibodies to the antigens tested were more frequent in MMN than in controls. Increased titres of anti-GM1 IgM were found in 48% of MMN patients with a specificity of 93% and PPV for MMN of 66%. Anti-GM1/GalC antibodies were present in all anti-GM1 positive MMN patients and in 11 additional patients (28%) with MMN raising the sensitivity of antibody testing to 75%. The specificity (85%) and PPV (59%) for MMN was, however, moderately reduced compared to anti-GM1 IgM, even if they rose with increasing anti-GM1/GalC titres. IgM antibodies to GM2, NS6S and galactocerebroside were found in 8%, 23% and 60% of MMN patients but had a low specificity and PPV for MMN. Conclusions Testing for anti-GM1/GalC IgM significantly increased the sensitivity of antibody testing in MMN compared to anti-GM1 alone (p=0.021) and may represent a preferred option for GM1 reactivity testing in MMN.

BackgroundWe reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening.MethodsBy March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1–60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up.ResultsTwenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1–57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7–60). Worsening occurred 1–24 months (median 4.5) after IVIg discontinuation and 1–31 months (median 14) after IVMP discontinuation (p=0.0126).ConclusionsA similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP.

In the present work we analyse one of the active normal faults affecting the central Apennines, i.e. the Mt. Morrone normal fault system. This tectonic structure, which comprises two parallel, NW-SE trending fault segments, is considered as potentially responsible for earthquakes of magnitude ≥ 6.5 and its last activation probably occurred during the second century AD. Structural observations performed along the fault planes have allowed to define the mainly normal kinematics of the tectonic structure, fitting an approximately N 20° trending extensional deformation. Geological and geomorphological investigations performed along the whole Mt. Morrone south-western slopes permitted us to identify the displacement of alluvial fans, attributed to Middle and Late Pleistocene by means of tephro-stratigraphic analyses and geomorphological correlations with dated lacustrine sequences, along the western fault branch. This allowed to evaluate in 0.4 ± 0.07 mm/year the slip rate of this segment. On the other hand, the lack of synchronous landforms and/or deposits that can be correlated across the eastern fault segment prevented the definition of the slip rate related to this fault branch. Nevertheless, basing on a critical review of the available literature dealing with normal fault systems evolution, we hypothesised a total slip rate of the fault system in the range of 0.4 ± 0.07 to 0.8 ± 0.09 mm/year. Moreover, basing on the length at surface of the Mt. Morrone fault system (i.e. 22–23 km) we estimated the maximum expected magnitude of an earthquake that might originate along this tectonic structure in the order of 6.6–6.7.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1 mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.

Data in the literature show that migraine tends to improve during pregnancy in most migrainous women. The aim of this Internet survey was to obtain the most likely cross section of the situation in the general population with respect to the presence and course of migraine in pregnancy. All women who participated were asked to answer questions pertaining to their history of pregnancy and headache. One thousand and eighteen women participated in the survey; only 775 met the eligibility criteria for inclusion. One hundred and ninety-five women (25.2 %) reported having had a headache only before pregnancy, 425 (54.8 %) before and during pregnancy, and 155 (20.0 %) only during pregnancy. Women suffering from headache before and/or during pregnancy were much more likely to have headaches with more migrainous features at the ID Migraine Screener test when compared to women whose headache began during pregnancy. “Definite migraines” were 277/620 (44.7 %) and 26/155 (16.8 %), respectively, in the two groups ( p  < 0.0001). Among the 620 females that suffered from headache before pregnancy, 375 (60.5 %) improved, 195 (31.5 %) showed complete resolution of the disorder, and 180 (29.0 %) had a reduction in headache frequency. Moreover, the multinomial logistic model (with headache pattern as dependent variable) proved fetal presentation as significant ( p  = 0.0042). Women with “new headache” (No/Yes pattern) had an OR (95 % CI) of 1.9 (1.2–3.0) of breech presentation at delivery versus those with a stable pattern of headache (Yes/Yes). Finally, women with not recent pregnancy stated they suffered from headache less than the women with recent pregnancy.