Altered synaptic glutamate homeostasis contributes to cognitive decline in young APP/PSEN1 mice.

Non-convulsive epileptiform activity is a common and under-studied comorbidity of Alzheimer's disease that may significantly contribute to onset of clinical symptoms independently of other neuropathological features such as ß-amyloid deposition. We used repeated treatment with low dose kainic acid (KA) to trigger sub-threshold epileptiform activity in young (less than 6 months) wild-type (WT) and APP/PSEN1 mice to test the role of disruption to the glutamatergic system in epileptiform activity changes and the development of memory deficits. Short-term repeated low-dose KA (five daily treatments with 5 mg/kg, IP) impaired long-term potentiation in hippocampus of APP/PSEN1 but not WT mice. Long-term repeated low-dose KA (fourteen weeks of bi-weekly treatment with 7.5-10 mg/kg) led to high mortality in APP/PSEN1 mice. KA treatment also impaired memory retention in the APP/PSEN1 mice in a Morris water maze task under cognitively challenging reversal learning conditions where the platform was moved to a new location. Four weeks of bi-weekly treatment with 5 mg/kg KA also increased abnormal spike activity in APP/PSEN1 and not WT mice but did not impact sleep/wake behavioral states. These findings suggest that hyperexcitability in Alzheimer's disease may indeed be an early contributor to cognitive decline that is independent of heavy ß-amyloid-plaque load, which is absent in APP/PSEN1 mice under 6 months of age.

Medical and endovascular treatments of symptomatic intracranial stenosis. A Bayesian network meta-analysis.

Intracranial stenosis is a well-established stroke risk factor with an increase of stroke recurrence or TIA up to 12.6% at 1 year. Treatments are different: medical and endovascular. We performed a multiple treatment comparison analysis to detect the best treatment in reducing the risk of stroke recurrence. We searched in Medline, Embase, Cochrane Central Register of Controlled Trials databases between 1979 and October 2017. Inclusion criteria were prospective randomized trials that evaluated patients with TIA or stroke due to intracranial stenosis and treated with different medical therapies and/or endovascular procedures. Primary endpoint was the recurrence of TIA or stroke in the territory of intracranial stenosis, while secondary endpoint was represented by any stroke or vascular death. Multiple treatment comparison meta-analysis based on a Bayesian fixed and random effects Poisson model was performed. Seven trials were included with a total of 1337 patients. At multiple treatment comparison, no significant differences between treatments were observed for both primary (median fixed effect standard OR: 0.40; 95%CI: 0.02-1.07) and secondary endpoints (median random effect standard OR: 1.17; 95%CI: 0.32-1.92). Treatment with aspirin alone ranked with high values both for primary and secondary endpoints (surface under the cumulative ranking curve of 70% and 82%, respectively). In patients with symptomatic intracranial stenosis, no differences between treatments were observed. However, aspirin alone was more effective than stenting in the reduction of TIA or stroke recurrences, with a better safety profile than oral anticoagulants.

Intravenous thrombolysis in stroke mimics: results from the SITS International Stroke Thrombolysis Register.

BACKGROUND AND PURPOSE: Patients with stroke mimics (SM), i.e. conditions with stroke-like symptoms, may risk harm if treated with intravenous thrombolysis (IVT). Current guidelines state low risk of intracerebral hemorrhage based on studies comprising a total of <400 SM cases. We aimed to compare safety and outcomes following IVT between patients with acute ischaemic stroke and mimicking conditions. METHODS: We included IVT-treated ischaemic stroke patients in the SITS International Stroke Thrombolysis Register 2003-2017, examined with magnetic resonance imaging 22-36 h after treatment. Outcomes were parenchymal hematoma (PH) after treatment, symptomatic intracerebral hemorrhage (SICH) per Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST), Second European Co-operative Stroke Study (ECASS II) and National Institutes of Neurological Disorders and Stroke Study (NINDS) criteria, death and modified Rankin Scale score (mRS) at 3 months. RESULTS: Of 10 436 patients, 429 mimics (4.1%) were identified. The most common types were functional (30.8%), migraine (17.5%) and seizure (14.2%). Patients with mimics had fewer cerebrovascular risk factors and lower median National Institutes of Health Stroke Scale score [7 (interquartile range, 5-10) vs. 8 (5-14), P < 0.001]. Among mimics versus stroke patients, PH was seen in 1.2% vs. 5.1% (P < 0.001), SICH NINDS in 0.5% vs. 3.9% (P < 0.001), SICH ECASS II in 0.2% vs. 2.1% (P = 0.007) and SICH SITS-MOST in 0% vs. 0.5% (P = 0.28). Modified Rankin Scale score 0-1 at 3 months was present in 84.1% vs. 57.7% (P < 0.001) and death within 3 months in 2.6% vs. 5.4% (P = 0.028) of mimics and stroke patients, respectively. CONCLUSIONS: This large observational study indicated that PH and SICH following IVT in patients with SM are uncommon.

Previous infection and the risk of ischaemic stroke in Italy: the IN2 study.

BACKGROUND AND PURPOSE: There is an increasing interest in new risk factors for ischaemic stroke. Acute and chronic infections could contribute to different aetiological mechanisms of atherosclerosis that lead to cerebrovascular disease. The aim of this study was to investigate the hypothesis that previous infections and Chlamydia pneumoniae in particular increase the risk of ischaemic stroke in the population. METHODS: This was a prospective case-control study involving 11 Italian stroke units. Controls were age- and sex-matched with cases, represented by patients admitted to hospital for acute ischaemic stroke. For each participant classical vascular risk factors and previous inflammatory and infectious events up to 1 month before were registered. Blood samples were collected to analyse inflammatory markers and titres of antibodies against C. pneumoniae. RESULTS: A total of 1002 participants were included (mean age 69 years) with 749 ischaemic stroke patients. Infections occurred within 1 month previously in 12% of the entire sample with a higher prevalence in the case group (14.4% vs. 3.9%). At multivariate analysis of the seropositivity of IgA antibodies against C. pneumoniae increased the risk of stroke significantly (relative risk 2.121; 95% confidence interval 1.255-3.584) and an early previous infection (up to 7 days before the event) contributed to a rise in probability of acute cerebral ischaemia (relative risk 3.692; 95% confidence interval 1.134-6.875). CONCLUSIONS: Early previous infections and persistent chronic infection of C. pneumoniae could contribute to increase the risk of ischaemic stroke significantly, in the elderly especially.

Chronic migraine in women is associated with insulin resistance: a cross-sectional study.

BACKGROUND AND PURPOSE: Migraine is a common neurological disorder. It can be divided into episodic migraine (EM) and chronic migraine (CM), based on headache frequency. Some studies have shown that insulin sensitivity is impaired in migraine; moreover, hypertension, diabetes and obesity are common in patients with CM. The aim of this study was to assess serum glucose, insulin levels and insulin resistance (IR) in a sample of episodic migraineurs, chronic migraineurs and non-pain healthy controls. METHODS: Eighty-three women with EM, 83 with CM and 83 healthy controls were recruited. Headache was diagnosed according to the latest International Classification of Headache Disorders 2 criteria. Waist circumference, body mass index (BMI) and blood pressure were measured. Checked metabolic parameters included fasting glucose, the 2 h 75 g oral glucose tolerance test (2 h OGTT), serum HbA1c, blood lipid profile, C-reactive protein and prolactin. The homeostasis model assessment formula was used to calculate IR. RESULTS: A significant prevalence of IR in CM was observed (P = 0.002). No significant associations were found with fasting glycaemia, the 2 h OGTT, HbA1c, blood lipid profile, C-reactive protein, prolactin and waist circumference. Obesity (BMI >30 kg/m(2)) was associated with an increased risk of CM [odds ratio (OR) 2.4]. When the outcome of interest was the association between IR and obesity, the OR was significantly increased compared with IR alone (OR = 13.2). CONCLUSION: This may suggest that CM is associated with IR status, particularly when it is in partnership with obesity.

Levetiracetam versus carbamazepine in patients with late poststroke seizures: a multicenter prospective randomized open-label study (EpIC Project).

BACKGROUND: Strokes are the leading cause of epileptic seizures in adults and account for 50% of seizures in those over the age of 65 years. The use of antiepileptic drugs to prevent recurrent poststroke seizures is recommended. METHODS: One hundred and twenty-eight patients with poststroke seizures were randomly allocated to treatment with either levetiracetam (LEV) or sustained-release carbamazepine (CBZ) in a multicenter randomized open-label study. After a titration study phase (2 weeks), the optimal individual dose of trial medication was determined and treatment was continued for another 52 weeks. The primary endpoint was defined as the proportion of seizure-free patients; the secondary endpoints were: evaluation of time recurrence to the first seizure, EEG tracings, cognitive functions and side effects. RESULTS: Of 128 patients, 22 discontinued the trial prematurely; thus a total of 106 patients (52 treated with LEV and 54 treated with CBZ) were included in the analysis. The results of the study were as follows: no significant difference in number of seizure-free patients between LEV and CBZ (p = 0.08); time to the first recurrence tended to be longer among patients on LEV; there was no correlation between the therapeutic effect and the EEG findings in either treatment group; LEV caused significantly fewer (p = 0.02) side effects than CBZ; attention deficit, frontal executive functions and functional scales (Activities of Daily Living and Instrumental Activities of Daily Living indices) were significantly worse in the CBZ group. CONCLUSIONS: This trial suggests that LEV may be a valid alternative to CBZ in poststroke seizures, particularly in terms of efficacy and safety. In addition, our results show that LEV has significant advantages over CBZ on cognitive functions. This trial also indicates that LEV in monotherapy is a safe and effective therapeutic option in elderly patients who have suffered epileptic seizures following a stroke.

In situ detection of lung cancer volatile fingerprints using bronchoscopic air-sampling.

Lung cancer diagnosis via breath analysis has to overcome some issues that can be summarized by two crucial points: (1) further developments for more performant breath sampling technologies; (2) discovering more differentiated volatile fingerprints to be ascribed to specific altered biological mechanisms. The present work merges these two aspects in a pilot study, where a breath volume, sampled via endoscopic probe, is analyzed by an array of non-selective gas sensors. Even if the original non-invasive methods of breath analysis has been laid in favour of the endoscopic means, the innovative technique here proposed allows the analysis of the volatile mixtures directly sampled near the tumor mass. This strategy could open the way for a better understanding of the already obtained discrimination among positive and negative cancer cases. The results obtained so far confirm the established discrimination capacity. This allows to discriminate the different subtypes of lung cancer with 75% of correct classification between adenocarcinoma and squamous cell carcinoma. This result suggests that a 'zoom-in' on the cancer settled inside the human body can increase the resolution power of key-volatiles detection, allowing the discrimination among different cancer fingerprints. We report this novel technique as a robust support for a better comprehension of the promising results obtained so far and present in literature; it is not to be intended as a replacement for non-invasive breath sampling procedure with the endoscope.

Incidence and predictors of acute symptomatic seizures after stroke.

OBJECTIVE: To assess incidence and predictors of acute symptomatic seizures in a prospective cohort of patients with first stroke. METHODS: Patients with first stroke hospitalized in 31 Italian centers were recruited. Relevant demographic data, disease characteristics, and risk factors were collected. Acute symptomatic seizures (≤7 days) were recorded and correlated to age, gender, family history of epilepsy, and vascular risk factors. RESULTS: A total of 714 patients (315 women, 399 men; age 27-97 years) were enrolled. A total of 609 (85.3%) had cerebral infarction (32 cerebral infarction with hemorrhagic transformation [CIHT]) and 105 (14.7%) primary intracerebral hemorrhage (PIH). A total of 141 (19.7%) had a large lesion (>3 cm) and 296 (41.5%) cortical involvement. Twelve patients reported family history of seizures. Forty-five patients (6.3%) presented acute symptomatic seizures, 24 with cerebral infarction (4.2%), 4 with CIHT (12.5%), and 17 (16.2%) with PIH. In multivariate analysis, compared to cerebral infarction, PIH carried the highest risk (odds ratio [OR] 7.2; 95% confidence interval [CI] 3.5-14.9) followed by CIHT (OR 2.7; 95% CI 0.8-9.6). Cortical involvement was a risk factor for PIH (OR 6.0; 95% CI 1.8-20.8) and for CI (OR 3.1; 95% CI 1.3-7.8). Hyperlipidemia (OR 0.2; 95% CI 0.03-0.8) was a protective factor for IPH. CONCLUSION: The incidence of acute symptomatic seizures is the highest reported in patients with first stroke with prospective follow-up. Hemorrhagic stroke and cortical lesion were independent predictors of acute symptomatic seizures. Hyperlipidemia was a protective factor for hemorrhagic stroke.

Bell's palsy: a manifestation of prediabetes?

BACKGROUND: Idiopathic peripheral facial nerve palsy or Bell's palsy (BP) is the most common cause of facial nerve palsy. OBJECTIVE: To evaluate the role of glucose metabolism abnormalities in BP. METHODS: We identified 148 patients with unilateral BP and 128 control subjects. In all we evaluated glucose level at fasting and after a 2-h oral glucose tolerance test (2h-OGTT). In addition we determined insulin resistance (IR), by HOMA-index. Patients and controls were divided in to two groups, according to their Body Mass Index (BMI). RESULTS: Following a 2h-OGTT, the prevalence of glucose metabolism abnormalities was significantly higher in patients with BP than in controls (P < 0.001). Impaired glucose tolerance (IGT) was found in 57 (38%) patients and in 23 (18%) controls, while a new-diagnosed DM (NDDM) was found in 29 (19%) patients and in 8 (6%) controls. The IR was significantly increased only in BP patients with BMI ≥ 24.9 (P = 0.005). BMI, waist circumference, blood pressure, tryglicerides, serum lipid, drugs use were not significantly different between patients and controls. CONCLUSIONS: In this study we found that prediabetes is frequently associated with facial palsy. We propose to perform a 2h-OGTT in patients with peripheral facial palsy and normal fasting glycaemia. HOMA-index should be evaluated in obese facial palsy patients.

Role of the corticotropin-releasing factor receptor type 2 in the control of food intake in mice: a meal pattern analysis.

The actions of corticotropin-releasing factor (CRF) and related peptides are mediated by two receptors (CRF(1) and CRF(2)). The respective role of each subtype in the control of food intake remains poorly known. In the present study, we examined the quantity and microstructure of ingestive behavior of knockout (KO) mice lacking CRF(2) receptors and their wild-type (WT) littermates. Under basal conditions, CRF(2) KO mice showed increased nocturnal food intake, evident as an increased zenith in circadian cosinor analysis of food intake. Microstructure analysis revealed that this greater food intake reflected increased meal size, rather than meal frequency, suggesting a decreased satiating value of food. Following acute restraint stress, CRF(2) KO mice showed an intact immediate anorectic response with increased latency to eat and decreased meal size. However, CRF(2) deletion abolished the prolonged phase of restraint-induced anorexia. CRF(2) KO mice did not differ from WT controls in feeding responses to food deprivation or injection of ghrelin receptor agonists. Independent of genotype, food deprivation increased food intake, with dramatic changes in meal size, meal frequency, water : food ratio and eating rate. Acyl-ghrelin or BIM-28131, a potent ghrelin analog, dose-dependently stimulated food intake by increasing meal size (ghrelin, BIM-28131) and meal number (BIM-28131), while slowing the average eating rate (BIM-28131) similarly in WT and KO mice. These results suggest that the CRF(2) receptor is involved in the control of meal size during the active phase of eating and following acute exposure to stress.

Subcortical ischaemic changes in young hypertensive patients: frequency, effect on cognitive performance and relationship with markers of endothelial and haemostatic activation.

Information on subcortical ischaemic changes (SIC) in young hypertensive patients is scarce. We evaluated the frequency of SIC at magnetic resonance imaging (MRI), the possible effect on cognition of these patients, and the role of plasma markers known as indicators of endothelial and haemostatic activation. Inclusion criteria were age

The spectrum of Notch3 mutations in 28 Italian CADASIL families.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cause of hereditary cerebrovascular disease. It results from mutations in the Notch3 gene, a large gene with 33 exons. A cluster of mutations around exons 3 and 4 was originally reported and limited scanning of these exons was suggested for the diagnosis in most cases. OBJECTIVE: To report Notch3 mutation analysis in 28 unrelated Italian CADASIL families from central and south Italy. RESULTS: The highest rate of mutations was found in exon 11 (21%) and only 18% of mutations were in exon 4. This may be related to the peculiar distribution of Notch3 mutations in the regions of origin of the families. CONCLUSIONS: The results suggest that limited scanning of exons 3 and 4 is inadvisable in CADASIL cases of Italian origin.

Unusual clincal presentation of cerebral-isolated sarcoidosis. Case report and review of the literature.

The authors report the case of a 31-year-old man, who presented an hemorrhagic onset of a cerebral-isolated sarcoidosis, to date never described in the literature. Unusual clinical manifestation, neuroradiological study and direct histological confirmation are presented. Moreover, Gallium-67 Single Photon Emission Computed Tomography (Ga-67 SPECT) contribution is indicated to complete the evaluation of patients with cerebral inflammatory lesions, such as neurosarcoidosis, and in cases of equivocal neuroradiological imaging, to evaluate uptake activity of the inflammatory tissue. The patient did well and reported no further progression of his disease during 7 months of follow-up.

Production of somatic hybrids between frost-tolerant Solanum commersonii and S. tuberosum: characterization of hybrid plants.

Somatic fusion of mesophyll protoplasts was used to produce hybrids between the frost-tolerant species Solanum commersonii (2n=2x=24) and dihaploid S. tuberosum (2n=2x=24). This is a sexually incompatible combination due to the difference in EBN (Endosperm Balance Number, Johnston et al. 1980). Species with different EBNs as a rule are sexually incompatible. Fifty-seven hybrids were analysed for variation in chromosome number, morphological traits, fertility and frost tolerance. About 70% of the hybrids were tetraploid, and 30% hexaploid. Chloroplast counts in stomatal guard cells revealed a low frequency of cytochimeras. The frequency of aneuploids was relatively higher at the hexaploid level (hypohexaploids) than at the tetraploid level (hypotetraploids). The somatic hybrids were much more vigorous than the parents, and showed an intermediate phenotype for several morphological traits and moderate to profuse flowering. Hexaploid hybrid clones were less vigorous and had a lower degree of flowering than the tetraploid hybrid clones. All of the hybrids were female fertile but male sterile except for one, which was fully fertile and self-compatible. Many seeds were produced on the latter clone by selfing and on the male-sterile clones by crossing. The somatic hybrid plants showed an introgression of genes for frost tolerance and an adaptability to cold from S. commersonii. Therefore, the use of these somatic hybrids in breeding for and in genetic esearch on frost tolerance and cold-hardening is suggested.

Correlates of adaptation to the sleep laboratory. Behavior, sleep organization, quantitative EEG.

The present study aims at establishing to what extent adaptation phenomena should be taken into consideration for the definition of an independent baseline in sleep research. To this purpose we have studied: (1) a standard battery of neuropsychological test evaluating performance, subjective assessments of moods and sleep quality; (2) classical sleep parameters; (3) data derived from quantitative analysis of sleep EEG. 19 young male volunteers have been recorded for consecutive nights; 7 of them underwent the recordings for 3, 8 for 6 and 4 for 10 nights. Results can be summarized as follows: (A) both interindividual and intraindividual variability show a progressively decreasing trend toward homogeneity for most of the explored parameters; (B) steady state is reached in different times for different groups of parameters; (C) an adequate group homogeneity was achieved from the 5th night onwards. Implications of these data in sleep studies, namely in sleep active drug research are discussed.

[Statistical study on the medical management of patients with epilepsy in a district of Reggio Calabria]. / Indagine statistica sulla gestione medica di pazienti con epilessia in un Comprensorio della regione Calabria.

The epilepsy service provided by 143 doctors in the district of Vibo Valentia (Calabria) which has a population of 180,000 was studied by a team of specially trained medical students. The answers to a questionnaire given in personal interviews were statistically processed and revealed: a) a 3-4% incidence of epilepsy corresponding closely to the national average (Almost all doctors questioned had epileptic patients). b) that only 3% of the doctors tested drug concentration in the blood, while 33% relied on regular EEG checks. c) that Depakin (valproic acid) was the drug most often used, followed by Metinal-Idontoine (phenytoin + barbiturate), Dintoine (phenytoin) and Gardenal (phenobarbital). Almost all doctors were in favour of refresher courses to improve the service to epileptic patients.