Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in Parkinson's disease before brain pathology.

Bowel inflammation, impaired intestinal epithelial barrier (IEB), and gut dysbiosis could represent early events in Parkinson's disease (PD). This study examined, in a descriptive manner, the correlation among enteric α-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T α-synuclein Tg mice were sacrificed at 3, 6, and 9 months of age to evaluate concomitance of enteric inflammation, IEB impairments, and enteric bacterial metabolite alterations during the early phases of α-synucleinopathy. The molecular mechanisms underlying the interplay between α-synuclein, activation of immune/inflammatory responses and IEB alterations were investigated with in vitro experiments in cell cultures. Tg mice displayed an increase in colonic levels of IL-1ß, TNF, caspase-1 activity and enteric glia activation since 3 months of age. Colonic TLR-2 and zonulin-1 expression were altered in Tg mice as compared with controls. Lipopolysaccharide levels were increased in Tg animals at 3 months, while fecal butyrate and propionate levels were decreased. Co-treatment with lipopolysaccharide and α-synuclein promoted IL-1ß release in the supernatant of THP-1 cells. When applied to Caco-2 cells, the THP-1-derived supernatant decreased zonulin-1 and occludin expression. Such an effect was abrogated when THP-1 cells were incubated with YVAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric α-synuclein accumulation contributes to compromise IEB through the direct activation of canonical caspase-1-dependent inflammasome signaling. These changes could contribute both to bowel symptoms as well as central pathology.

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD.

Methods for analysis of brain connectivity: An IFCN-sponsored review.

The goal of this paper is to examine existing methods to study the "Human Brain Connectome" with a specific focus on the neurophysiological ones. In recent years, a new approach has been developed to evaluate the anatomical and functional organization of the human brain: the aim of this promising multimodality effort is to identify and classify neuronal networks with a number of neurobiologically meaningful and easily computable measures to create its connectome. By defining anatomical and functional connections of brain regions on the same map through an integrated approach, comprising both modern neurophysiological and neuroimaging (i.e. flow/metabolic) brain-mapping techniques, network analysis becomes a powerful tool for exploring structural-functional connectivity mechanisms and for revealing etiological relationships that link connectivity abnormalities to neuropsychiatric disorders. Following a recent IFCN-endorsed meeting, a panel of international experts was selected to produce this current state-of-art document, which covers the available knowledge on anatomical and functional connectivity, including the most commonly used structural and functional MRI, EEG, MEG and non-invasive brain stimulation techniques and measures of local and global brain connectivity.

Cortical connectivity and memory performance in cognitive decline: A study via graph theory from EEG data.

Functional brain abnormalities including memory loss are found to be associated with pathological changes in connectivity and network neural structures. Alzheimer's disease (AD) interferes with memory formation from the molecular level, to synaptic functions and neural networks organization. Here, we determined whether brain connectivity of resting-state networks correlate with memory in patients affected by AD and in subjects with mild cognitive impairment (MCI). One hundred and forty-four subjects were recruited: 70 AD (MMSE Mini Mental State Evaluation 21.4), 50 MCI (MMSE 25.2) and 24 healthy subjects (MMSE 29.8). Undirected and weighted cortical brain network was built to evaluate graph core measures to obtain Small World parameters. eLORETA lagged linear connectivity as extracted by electroencephalogram (EEG) signals was used to weight the network. A high statistical correlation between Small World and memory performance was found. Namely, higher Small World characteristic in EEG gamma frequency band during the resting state, better performance in short-term memory as evaluated by the digit span tests. Such Small World pattern might represent a biomarker of working memory impairment in older people both in physiological and pathological conditions.

Small-worldness characteristics and its gender relation in specific hemispheric networks.

Aim of this study was to verify whether the topological organization of human brain functional networks is different for males and females in resting state EEGs. Undirected and weighted brain networks were computed by eLORETA lagged linear connectivity in 130 subjects (59 males and 71 females) within each hemisphere and in four resting state networks (Attentional Network (AN), Frontal Network (FN), Sensorimotor Network (SN), Default Mode Network (DMN)). We found that small-world (SW) architecture in the left hemisphere Frontal network presented differences in both delta and alpha band, in particular lower values in delta and higher in alpha 2 in males respect to females while in the right hemisphere differences were found in lower values of SW in males respect to females in gamma Attentional, delta Sensorimotor and delta and gamma DMNs. Gender small-worldness differences in some of resting state networks indicated that there are specific brain differences in the EEG rhythms when the brain is in the resting-state condition. These specific regions could be considered related to the functions of behavior and cognition and should be taken into account both for research on healthy and brain diseased subjects.

Efficacy of a dual chamber defibrillator with atrial antitachycardia functions in treating spontaneous atrial tachyarrhythmias in patients with life-threatening ventricular tachyarrhythmias.

BACKGROUND: Atrial fibrillation has a high incidence in patients wearing an implantable cardioverter defibrillator for ventricular tachyarrhythmias and may lead to palpitations, heart failure, angina, stroke and inappropriate defibrillator discharge. The aim of the study was to evaluate the efficacy of a dual chamber defibrillator with atrial antitachycardia functions in treating spontaneous atrial tachyarrhythmias. METHODS: One hundred and twelve patients, 88 male, mean age 64+/-11 years, were enrolled. Seventy-six had ischaemic heart disease, 21 idiopathic dilated cardiomyopathy, nine other heart diseases, six no structural heart disease. The mean left ventricular ejection fraction was 40+/-11%. Sixty-two had prior atrial tachyarrhythmias. RESULTS: Follow-up lasted 11+/-9 months (range 1-42). Among 933 ventricular tachyarrhythmia episodes, 100% of ventricular fibrillation and 92% of ventricular tachycardia were successfully cardioverted. Among 414 detected sustained atrial tachyarrhythmias, 195 were classified as atrial tachycardia (47.1%), 192 as atrial fibrillation (46.4%) and 27 (6.5%) as sinus rhythm. The detection-positive predictive value was 93.5%. Therapy success rates: antitachy pacing on atrial tachycardia = 71.3% (crude estimate); 66.1% (adjusted estimate); 50 Hertz on atrial fibrillation=36.2% (crude estimate); 13.5% (adjusted estimate); atrial shock on atrial fibrillation = 62.5% (mean energy 7.8+/-14.1J). Shock efficacy was 32% when delivered energy was < or = 2 atrial defibrillation threshold at implant and 92% when >2. Duration of successfully treated atrial episodes was significantly lower than that of unsuccessfully treated (6+/-26 min vs 42+/-60). CONCLUSIONS: Atrial antitachy pacing and shock therapies demonstrated very high efficacy in treating atrial tachyarrhythmias in defibrillator patients.

Paroxysmal atrial fibrillation in patients paced for atrioventricular block. Comparison between DDD and VDD single-lead pacing system.

BACKGROUND: Paroxysmal atrial tachyarrhythmias have been frequently detected in patients paced for atrioventricular block. However, it is not yet clear which is the actual incidence of such arrhythmias and if they were preexisting but not recognized, or if they could be related to the device. METHODS: One hundred and forty-five patients with a diagnosis of second or third degree atrioventricular block were enrolled into the study. One hundred and twenty-four received a pacemaker Medtronic Thera DDD and 21 a Medtronic Thera VDD. High rate atrial episodes were evaluated for 3 months after enrollment. Atrial electrograms documenting paroxysmal atrial fibrillation (AF) were stored and programming of atrial sensitivity and pacemaker diagnostics was very strict in order to exclude short and false positive AF episodes. RESULTS: Thirty-six patients (35%) in the DDD group and 8 (42%) in the VDD group presented with AF (p = NS). The mean number o

Tumor extension along percutaneous transhepatic biliary drainage tracts.

Percutaneous Transhepatic Biliary Catheterization is commonly employed in the diagnosis and management of obstructive jaundice associated with malignant lesions. Tumor manipulation as an effort to obtain a histological diagnosis or to establish short or long-term internal-external biliary drainage is liable to disseminate the malignancy along the catheter tract. Two cases of malignant seeding of the catheter tract after biliary drainage have been observed.

Diagnosis of endometrial carcinoma and its precursors by means of cytologic examination of jet-washing material.

Experience with cytologic examination of 138 consecutive jet washings showed the value of the technique as a method of screening for endometrial carcinoma in symptomatic and at-risk patients. In the 127 adequate specimens obtained (92%), all 16 endometrial carcinomas were diagnosed cytologically. The necessity of physician experience in sampling as well as good cytopreparatory techniques in the use of jet washings is emphasized. A dual preparatory routine, including the use of Millipore filter preparations to evaluate cellularity and the type of clusters and the use of smears on chilled slides to evaluate cellular details, was found to be optimal.