Amyloid prefibrillar oligomers: The surprising commonalities in their structure and activity

It has been proposed that a "common core" of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer's, Parkinson's, type II diabetes and Creutzfeldt-Jacob's Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca2+ influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores. At the same time, the neuron membrane composition and its chemical microenvironment seem to play a pivotal role. In fact, the brain of AD patients contains increased fractions of anionic lipids able to favor cationic influx. However, up to now the existence of a specific "common structure" of the toxic aggregate, and a "common mechanism" by which it induces neuronal damage, synaptotoxicity and impaired synaptic transmission, is still an open hypothesis. In this review, we gathered information concerning this hypothesis, focusing on the proteins linked to several amyloid diseases. We noted commonalities in their structure and membrane activity, and their ability to induce Ca2+ influx, neurotoxicity, synaptotoxicity and impaired synaptic transmission

Brainstem evoked potentials and magnetic resonance imaging abnormalities in differential diagnosis of intracranial hypotension

Objective: To compare brainstem acoustic evoked potentials (BAEP)and magnetic resonance imaging (MRI)in the differential diagnosis of intracranial hypotension (IH), Chiari malformation (CM)and sensorineural hearing loss (SNHL). Methods: BAEP were recorded in 18 IH, 18 CM, 20 SNHL patients and 52 controls. MRI were acquired in all IH and CM patients. Results: Abnormal BAEP were observed in 94% of IH patients, in 33% of CM and 70% of SNHL patients. After recovery from IH, BAEP abnormalities disappeared. Internal auditory canal (IAC)MRI abnormalities were described in 88% of IH patients. MRI signs of IH were observed in 33\u201378% in IH patients, but the most frequent MRI sign was 8th nerve T2 hyperintensity, with contrast enhancement in T1 sequences. This finding, combined with wave I latency, yielded highest specificity and sensitivity for IH diagnosis. Conclusions: Our study points out how IH can be effectively distinguished from CM and SNHL through the contribution of neurophysiology and MRI; in particular, evaluation of the 8th nerve achieves a high sensitivity and specificity in patients with IH. Further studies are required to examine the combined use of BAEP recordings ad MRI in diagnosis and monitoring of patients affected by IH

Prolonged epileptic discharges predict seizure recurrence in JME: Insights from prolonged ambulatory EEG

Objective: Markers of seizure recurrence are needed to personalize antiseizure medication (ASM) therapy. In the clinical practice, EEG features are considered to be related to the risk of seizure recurrence for genetic generalized epilepsies (GGE). However, to our knowledge, there are no studies analyzing systematically specific EEG features as indices of ASM efficacy in GGE. In this study, we aimed at identifying EEG indicators of ASM responsiveness in Juvenile Myoclonic Epilepsy (JME), which, among GGE, is characterized by specific electroclinical features. Methods: We compared the features of prolonged ambulatory EEG (paEEG, 22 h of recording) of JME patients experiencing seizure recurrence within a year (“cases”) after EEG recording, with those of patients with sustained seizure freedom for at least 1 year after EEG (“controls”). We included only EEG recordings of patients who had maintained the same ASM regimen (dosage and type) throughout the whole time period from the EEG recording up to the outcome events (which was seizure recurrence for the “cases”, or 1-year seizure freedom for “controls”). As predictors, we evaluated the total number, frequency, mean and maximum duration of epileptiform discharges (EDs) and spike density (i.e. total EDs duration/artifact-free EEG duration) recorded during the paEEG. The same indexes were assessed also in standard EEG (stEEG), including activation methods. Results: Both the maximum length and the mean duration of EDs recorded during paEEG significantly differed between cases and controls; when combined in a binary logistic regression model, the maximum length of EDs emerged as the only valid predictor. A cut-off of EDs duration of 2.68 seconds discriminated between cases and controls with a 100% specificity and a 93% sensitivity. The same indexes collected during stEEG lacked both specificity and sensitivity. Significance: The occurrence of prolonged EDs in EEG recording might represent an indicator of antiepileptic drug failure in JME patients

Vaccinating Italian infants with a new multicomponent vaccine (Bexsero®) against meningococcal B disease: A cost-effectiveness analysis

This is the final version of the article. Available from the publisher via the DOI in this record.The European Medicines Agency has approved a multicomponent serogroup B meningococcal vaccine (Bexsero®) for use in individuals of 2 months of age and older. A cost-effectiveness analysis (CEA) from the societal and Italian National Health Service perspectives was performed in order to evaluate the impact of vaccinating Italian infants less than 1 y of age with Bexsero®, as opposed to non-vaccination. The analysis was carried out by means of Excel Version 2011 and the TreeAge Pro® software Version 2012. Two basal scenarios that differed in terms of disease incidence (official and estimated data to correct for underreporting) were considered. In the basal scenarios, we considered a primary vaccination cycle with 4 doses (at 2, 4, 6 and 12 months of age) and 1 booster dose at the age of 11 y, the societal perspective and no cost for death. Sensitivity analyses were carried out in which crucial variables were changed over probable ranges. In Italy, on the basis of official data on disease incidence, vaccination with Bexsero® could prevent 82.97 cases and 5.61 deaths in each birth cohort, while these figures proved to be three times higher on considering the estimated incidence. The results of the CEA showed that the Incremental Cost Effectiveness Ratio (ICER) per QALY was €109,762 in the basal scenario if official data on disease incidence are considered and €26,599 if estimated data are considered. The tornado diagram indicated that the most influential factor on ICER was the incidence of disease. The probability of sequelae, the cost of the vaccine and vaccine effectiveness also had an impact. Our results suggest that vaccinating infants in Italy with Bexsero® has the ability to significantly reduce meningococcal disease and, if the probable underestimation of disease incidence is considered, routine vaccination is advisable.The study was financed by the Italian Ministry of University and Research (MIUR, project PRIN 2009; Grant number: 2009ZPM4×4)

The interplay of perceived risks and benefits in deciding to become vaccinated against COVID-19 while pregnant or breastfeeding: A cross-sectional study in Italy.

The present study examined the role of the perception of risks and benefits for the mother and her babies in deciding about the COVID-19 vaccination. In this cross-sectional study, five hypotheses were tested using data from a convenience sample of Italian pregnant and/or breastfeeding women (N = 1104, July–September 2021). A logistic regression model estimated the influence of the predictors on the reported behavior, and a beta regression model was used to evaluate which factors influenced the willingness to become vaccinated among unvaccinated women. The COVID-19 vaccination overall risks/benefits tradeoff was highly predictive of both behavior and intention. Ceteris paribus, an increase in the perception of risks for the baby weighed more against vaccination than a similar increase in the perception of risks for the mother. Additionally, pregnant women resulted in being less likely (or willing) to be vaccinated in their status than breastfeeding women, but they were equally accepting of vaccination if they were not pregnant. COVID-19 risk perception predicted intention to become vaccinated, but not behavior. In conclusion, the overall risks/benefits tradeoff is key in predicting vaccination behavior and intention, but the concerns for the baby weigh more than those for the mother in the decision, shedding light on this previously neglected aspect

Daytime sleepiness in de novo untreated patients with epilepsy.

The aims of our study were to evaluate excessive daytime sleepiness in a group of de novo untreated people with epilepsy using a comprehensive and standardized approach, including subjective evaluation and neurophysiological and performance tests, and to compare these results with those obtained in a control group. Forty-seven patients with epilepsy (17 affected by primary generalized epilepsy and 30 by partial epilepsy), with a new epilepsy diagnosis and never treated, and 44 controls underwent Multiple Sleep Latency Test (preceded by nocturnal polysomnography), simple/complex visual reaction times, and Epworth Sleepiness Scale evaluation. Newly diagnosed and drug-free patients with epilepsy did not differ from controls in any of the tests performed to evaluate daytime sleepiness. In clinical practice, daytime sleepiness is a well-known and frequent complaint of patients with epilepsy, but different mechanisms and causes, such as associated psychiatric or sleep disorders, nocturnal seizures, sleep fragmentation, and antiepileptic drugs, must be taken into account. Excessive daytime sleepiness should not be considered an unavoidable consequence of epilepsy. Thus, a complete diagnostic work-up in patients with epilepsy and sleepiness should be undertaken whenever possible

Perampanel outcomes at different stages of treatment in people with focal and generalized epilepsy treated in clinical practice: Evidence from the PERMIT study

IntroductionThe PERMIT study is the largest pooled analysis of perampanel (PER) clinical practice data conducted to date.MethodsThis post-hoc analysis of PERMIT investigated the effectiveness, safety and tolerability of PER when used as early add-on therapy (after failure of one or two previous antiseizure medications) in comparison with late add-on therapy (after failure of three or more previous antiseizure medications). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness was assessed by seizure type (total seizures, focal seizures, generalized tonic-clonic seizures [GTCS]) and assessments included seizure freedom rate and responder rate. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.ResultsThe Full Analysis Set included 1184 and 2861 PWE treated with PER as early and late add-on therapy, respectively. Compared to the late add-on subgroup, the early add-on subgroup was characterized by later mean age at epilepsy onset, shorter mean duration of epilepsy, lower rates of intellectual disability and psychiatric comorbidity, and lower frequency of seizures per month, suggesting a less severe form of epilepsy in this subgroup. After 12 months, retention was significantly higher in the early versus late add-on subgroup (67.7% vs. 62.4%; p = 0.004). At the last visit, responder rates in the early versus late add-on subgroup were significantly higher for total seizures (68.2% vs. 39.3%; p &amp;lt; 0.001), focal seizures (65.0% vs. 36.8%; p &amp;lt; 0.001) and GTCS (83.7% vs. 67.2%; p &amp;lt; 0.001), as were seizure freedom rates (total seizures, 35.9% vs. 11.9% [p &amp;lt; 0.001]; focal seizures, 29.4% vs. 8.7% [p &amp;lt; 0.001]; GTCS, 69.0% vs. 48.1% [p &amp;lt; 0.001]). Incidence of AEs was significantly lower in the early versus late add-on subgroup (42.1% vs. 54.7%; p &amp;lt; 0.001), as was the rate of discontinuation due to AEs over 12 months (15.0% vs. 18.1%; p = 0.031).DiscussionThis study demonstrated that PER was effective and generally well tolerated when initiated as early or late add-on therapy, but it was significantly more effective and better tolerated when initiated early. These findings support PER's use as a broad-spectrum, early add-on therapy for use in PWE with focal and generalized seizures.</jats:sec

Italian Association of Sleep Medicine (AIMS) position statement and guideline on the treatment of menopausal sleep disorders

Insomnia, vasomotor symptoms (VMS) and depression often co-occur after the menopause, with consequent health problems and reductions in quality of life. The aim of this position statement is to provide evidence-based advice on the management of postmenopausal sleep disorders derived from a systematic review of the literature. The latter yielded results on VMS, insomnia, circadian rhythm disorders, obstructive sleep apnea (OSA) and restless leg syndrome (RLS). Overall, the studies show that menopausal hormone therapy (MHT) improves VMS, insomnia, and mood. Several antidepressants can improve insomnia, either on their own or in association with MHT; these include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and mirtazapine. Long-term benefits for postmenopausal insomnia may also be achieved with non-drug strategies such as cognitive behavioral therapy (CBT) and aerobic exercise. Continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) both reduce blood pressure and cortisol levels in postmenopausal women suffering from OSA. However, the data regarding MHT on postmenopausal restless legs syndrome are conflicting